The Adaptable MHC Fold. Structure and Function of Nonclassical and MHC Class I-Like Molecules.

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MHC Class ILike Molecules

Erin J. Adams1,2 and Adrienne M. Luoma2
1
Department of Biochemistry and Molecular Biology, 2 Committee on Immunology,
University of Chicago, Chicago, Illinois 60637; email: ejadams@uchicago.edu,
aluoma@uchicago.edu
Annu. Rev. Immunol. 2013. 31:52961 Keywords

First published online as a Review in Advance on evolution, antigen presentation, T cell receptor, NK receptors,
January 7, 2013
homeostasis
The Annual Review of Immunology is online at
immunol.annualreviews.org Abstract
This articles doi:
The MHC fold is found in proteins that have a range of functions in
10.1146/annurev-immunol-032712-095912
the maintenance of an organisms health, from immune regulation to fat
Copyright c 2013 by Annual Reviews.
metabolism. Well adapted for antigen presentation, as seen for peptides
All rights reserved
in the classical MHC molecules and for lipids in CD1 molecules, the
MHC fold has also been modied to perform Fc-receptor activity (e.g.,
FcRn) and for roles in host homeostasis (e.g., with HFE and ZAG).
The more divergent MHC-like molecules, such as some of those that
interact with the NKG2D receptor, represent the minimal MHC fold,
doing away with the 3 domain and 2 m while maintaining the 1/2
platform domain for receptor engagement. Viruses have also co-opted
the MHC fold for immune-evasive functions. The variations on the
theme of a -sheet topped by two semiparallel -helices are discussed
in this review, highlighting the fantastic adaptability of this fold for
good and for bad.
529
INTRODUCTION functions, including as ligands for the activating

receptor NKG2D, T cell ligands, and lipid-
Proteins containing the major histocompatibil-
presenting molecules and even as neuromodu-
Human leukocyte ity complex (MHC) fold form a diverse fam-
antigen (HLA): refers lators or pheromone receptors (reviewed in 3).
ily encoded by genes spread throughout the
to the human MHC Most of these proteins have representatives in
genome. The more recently evolved, classical
and its MHC proteins both human and mouse, although it is unclear
MHC molecules are located within the MHC
Anchor residues: whether in every case their function is preserved
region, found on chromosome 6 in humans and
conserved positions in in the two species. The focus of this review is
chromosome 17 in mice (Figure 1). These pro-
a peptide repertoire on the biology and structure of these diverse
for a given MHC allele teins, represented by highly polymorphic class
nonclassical and MHC class Ilike proteins; ow-
that anchor the I and class II types, serve to present peptides of

peptide in the MHC ing to space constraints, discussion centers on
varying size to T cells and are an integral
groove molecules that have had structural elucidation.
part of vertebrate adaptive immunity. Classi-
cal class I molecules have an MHC fold de-
rived from a single polypeptide chain (heavy

chain) that associates with the nonpolymorphic ARCHITECTURE OF THE
2 -microglobulin (2 m) subunit to form a sta- MHC FOLD
ble, cell surface protein; class II molecules, in The rst structural determination of an
contrast, use two polypeptide chains ( and ) MHC molecule was the human classical
to form their MHC fold (1). Nonpolymorphic class I molecule, HLA-A2 (4). This pivotal
representativestermed nonclassical MHC structure demonstrated how classical MHC
for those encoded by genes located within the molecules could bind peptide and established
MHC region and MHC-like molecules for a model for understanding the structures of all
those outside the MHCexist for both class MHC-related proteins. Class I molecules have
I and class II proteins, the most diverse being the characteristic MHC fold composed of a
those related to the MHC class I molecules. -sheet topped by two semiparallel -helices
Most of these nonclassical and MHC class I (Figure 3, upper left); the canonical MHC class
like proteins have functions other than pep- I fold is formed by two semisymmetrical do-
tide presentation; these functions can be im- mains, 1 and 2; each domain contributes an
mune or nonimmune related. Although non- -helix and four strands of a -sheet (Figure 3,
classical proteins are encoded within the MHC, bottom). This basic architecture is also reected
the MHC-like representatives are distributed in MHC class II molecules, where the 1 and
across chromosomes 1, 2, 7, and 19 in humans 2 domains are instead 1 and 1 domains
and 3, 5, 7, 10, and 20 in mice (Figure 1). The encoded by the - and -chains, respectively.
evolution of the genes encoding these proteins There are slight variations on the number of
has been dynamic, at the level of both chro- -strands and conformation of the -helices
mosomes and loci, with a related diversication (in particular the 1/2-helix) between class I
of their protein structure, adapted to the many and class II, yet the overall structure is remark-
roles these proteins play in the host organism. ably similar between the two molecules. This
The phylogenetic relationship of the MHC fold is further reected in the diverse reper-
class Irelated proteins is shown in Figure 2. toire of nonclassical MHC molecules; however,
The classical, peptide-presenting MHC class I their structural and biochemical differences suit
molecules form the most compact area of the them for their highly divergent functional roles.
tree, indicating their close amino acid homol- The classical MHC class I and class II fold
ogy, which could support the argument that is well adapted toand in fact dependent on
they are evolutionarily recent (2). The major presenting peptides; these small fragments of
branches in the tree are composed of distant proteins from both self and nonself proteins
class I relatives, which have evolved specialized form an integral part of stable classical MHC
530 Adams Luoma

proteins. Peptides are bound between the two Human Mouse

-helices in a shallow groove that is either en- K
Chr6
0.1 Mb
closed at each end (class I) (Figure 3, upper DP2
DP1 Chr17
right) or open (class II); peptides for class I DO O
molecules are usually from 8 to 10 amino acids DM M M1,2
Class II
long, whereas class II molecules can present DO
DQ2
peptides ranging from 8 to 20 amino acids. O
DQ1 A
A
Each MHC molecule can form stable com- DR1
DR5
E
E2 E
plexes with hundreds or thousands of differ- DR
ent peptides, sharing only a few conserved an-
Class III
D/L
chor residues that are accommodated in pockets Q1
Q4
Q2
present in the MHC groove. The chemical and Q10
Qa-2
MICB
structural makeup of the groove and its pockets
MICA
differs in each MHC molecule and determines HLA-B

HLA-C
the repertoire of peptides that each can bind.
The composite surface formed by the MHC
T24
molecule and peptide is surveyed by T cells Qa-1 T22
T9
via their T cell receptor (TCR); nonself MHC- T10
T3(TL)
Class I
peptide (MHCp) complexes can initiate T cell M10.2

M10.1
responses that lead to transplant and tumor re- M10.3
M10.4
jection, antiviral responses, and the recruitment
HLA-E M11
and modulation of other immune cells. M9
M1
M10.5
M10.6
THE NONCLASSICAL
M5
PEPTIDE-PRESENTING
0.5 Mb
HLA-A
MOLECULES
0.5 Mb
HLA-G
M3
Closest to the classical class I proteins in prox- HLA-F
imity and homology are HLA-E, F, and G in M2
humans and M3 and the Qa and Q families HFE
in mice (Figure 2). Structures have been de-
~124 Mb
termined for HLA-E (510), HLA-G (1114),
M3 (15), Qa-1 (16), and Qa-2 (17). These pro- Rae-1 Rae-1
teins, like their close classical relatives, retain ULBP4
ULBP5 Rae-1 Rae-1
ULBP2 Rae-1
ULBP1
ULBP6 MULT1
Figure 1 ULBP3
Genomic organization of the human and mouse
major histocompatibility complex (MHC) and
chromosomal regions of MHC class Ilike proteins.
H60b H60a
The class I and class II regions are shown in
lavender and lime, respectively. Regions encoding Chr10
the NKG2D ligands (ULBP in human, Rae-1 and CD1d
H60 in mouse) are highlighted in pink. The CD1 CD1a
and MR1 genomic region is shown in peach. CD1c
CD1b CD1d1 CD1d2
Nonclassical and MHC-like gene names are in bold. CD1e
0.1 Mb
0.1 Mb
The distance scale (in megabases, Mb) is shown for ~23 Mb ~70 Mb
each section (indicated by dashed bars). The
chromosomal location of each genomic region is MR1 MR1
Chr1 Chr3
indicated in red text.
www.annualreviews.org Nonclassical and MHC-Like Proteins 531

C
d MH
lize s I
e cia o l o g
Sp h o m
11
9
1 mM
10.5
mT 9 10.3 10.2 10.4
22
10 10.1
5 10.6
Sp h o m
100 mT24
ec o l
h ZAG
mT3(TL) 98
ial o g
100 m
mM2
ize s I
dM I
100 h
77
100
m MR1 h
m HFE
HC
* * 100
90
*** m1 MILL
66 100
** m2
100 hA
* 69
73 hB MIC
63
100 h
m FcRN
H2
mole esenting
D
98 99
mQa-2 L 100
l
h
p e p t i nclassica
K 97
4 m EPCR
cules
63 80
mQ 10 72
2 1 mCD1d
de -pr
53 64
d 2
1
ul g
No
ec tin
mQa-1 98
es
ol n
E hCD1
m rese
F e
G C
A B
HC p
b
M id-
mM3
HLA
1 2 65 c
p
4 3 mMULT1
Li
100

hULBP
0.2
mRAE1
100 0.2
a ds * bootstrap values < 50%

c b
ig an
mH60
Dl
G2
NK
Figure 2
The phylogenetic relationships of the classical, nonclassical, and MHC class Ilike proteins. This phylogenetic tree was inferred using
the neighbor-joining method. The tree and its branches are drawn to scale; the length of each branch is proportional to the
evolutionary distance as calculated by the p-distance method. Condence in the groupings was measured by the bootstrapping method,
and values are shown at the key nodes. Those with less than 50% condence are indicated with an asterisk. The scale is indicated at the
base of the gure and indicates the number of amino acid differences per site. Note the expanded scale of the classical/nonclassical
grouping due to illustrative enlargement. Evolutionarily related groupings are highlighted, with their distance from the classical class I
proteins related to the visual spectrum, with pink/orange representing more closely related and blue/purple indicating more distantly
related groupings. The labeled groupings in red represent the organizing principle used in this review, and the proteins that have been
structurally elucidated and that are discussed in the text are indicated by bold text and a red circle.
532 Adams Luoma

HLA-A2 HLA-A2/HTLV-Tax
1
2
1
2
Figure 3
Structure of the classical MHC class I molecule HLA-A2. HLA-A2 (PDB ID: 1DUZ) is shown as ribbon
(upper left and bottom panels) and surface (upper right) and is colored according to its domain structure (as
labeled in the gure). The bottom panels show the semisymmetrical relationship between the 1 and 2
domains, as noted in the original publication (4). The surface representation includes the HTLV-Tax
peptide, colored in yellow and shown as sticks and dots. Water molecules involved in peptide binding are
shown in blue spheres and dots. Atoms are colored as follows: red, oxygen; blue, nitrogen; yellow, carbon. All
structure representations in this review were made with the program PymolTM .
Paralogs: a pair of
genes present in a
the ability to bind and present peptides, al- roles have been conserved since the divergence species that are derived
though distinct structural features concentrated of the mouse and human species, 60 Mya. through duplication
in the peptide-binding region and their low from an ancestral gene
polymorphism distinguish these proteins from Orthologs: genes that
classical MHC molecules. Whereas the genes HLA-E and Qa-1 are present in two
different species that
that encode the classical class I proteins (HLA- Both HLA-E and Qa-1 preferentially present derive from the same
A, -B, -C in human and H2-K, D, and L in peptides derived from leader sequences of common ancestor
mouse) are likely paralogs between mouse and other classical class I molecules (Figure 4a) Root mean square
human, direct orthology has been suggested be- (20, 21). Their peptide-binding grooves are deviation (RMSD):
tween HLA-E and Qa-1 (18), whereas func- highly similar, with a RMSD of 0.9 A, as are average distance
tional homology is apparent between HLA-G the sequences and bound conformation of the between the C atoms
and Qa-2 (19), suggesting that their functional of two superimposed
leader peptides they present (RMSD 0.6 A)
structures

a b
1 1
2 2
Qa-1 CD94/ Qa-2

HLA-E HLA-E NKG2A HLA-G
1
HLA-G
2
2m
P8
D2
3
HLA-E:
LILRB2
Qa1: VMAPRTLFL KK50.4
AMAPRTLLL VTAPRTLLL TCR
HLA-E/ D1
VMAPRALLL
UL40peptide
Figure 4
The peptide-presenting nonclassical class I molecules, HLA-E, Qa-1, HLA-G, and Qa-2. (a) Comparison of the structures of HLA-E
( pale cyan ribbon, PDB ID: 3BZE) and Qa-1 ( pink ribbon, PDB ID: 3VJ6) are shown in the upper left panel, including their bound
peptides. The lower left panel shows the close conformational similarity of Qa-1- and HLA-E-bound peptides, generated through
alignment of the class I heavy chains (additional PDB IDs: 1KTL and 3BZF). Peptides are shown as sticks, with atom colorings as
described in Figure 3, except carbons are colored as indicated by the sequence of peptides at the bottom. The right column of panel a
shows a surface representation of HLA-E/peptide (shown in white) and the footprints of the CD94/NKG2A receptor (top, colored in
pale green, PDB ID: 2ESV) and the KK50.4 TCR (bottom, colored in yellow, PDB ID: 3CDG). The position of the P8 residue of the
peptide is circled in red. (b) Top: structural comparison of HLA-G (orange ribbon, PDB ID: 1YDP) and Qa-2 ( yellow ribbon, PDB ID:
1K8D) and their respective peptides. Bottom: complex between HLA-G (orange ribbon) and the LILRB2 receptor (lavender ribbon, PDB
ID: 2DYP).
(Figure 4a, bottom left) (16). Five conserved for the family of CD94/NKG2 receptors
hydrophobic pockets in the grooves of HLA-E expressed by natural killer (NK) and T cells
and Qa-1 anchor the peptides via residues 2, 3, (22, 23). Downregulation of classical class I
6, 7, and 9; an extensive hydrogen-bonding net- protein productiona common strategy for
work between the heavy chain and the peptide some bacterial and viral infectionsdisrupts
main chain as well as conserved charged inter- the availability of leader sequences and thus the
actions further stabilize the peptides. Most of proper expression of Qa-1 and HLA-E on the
the heavy chain residues contributing to these cell surface. Without the inhibitory signal that
interactions are identical between HLA-E and these molecules provide for the CD94/NKG2A
Qa-1. Like classical class I molecules, peptide is receptor, cytolytic cells such as NK cells can
a required component for complex stability on detect and eliminate compromised host cells.
the cell surface; that these peptides derive from The respective complexes of CD94/
leader sequences of classical proteins provides NKG2A with Qa-1 and HLA-E are recognized
a link to the primary function of HLA-E and with similar afnities, although the recognition
Qa-1 in the innate immune response as ligands of Qa-1 was slightly weaker (17 M) compared
534 Adams Luoma

with HLA-E (5 M) (16). Unlike other highly the key amino acid position that differs between
conserved systems, there is no cross-reactivity leader sequences: P8. Indeed, all three CDR
between human and mouse CD94/NKG2 loops focused on this position, highlighting the
receptors. This lack of cross-reactivity is likely importance of subtle changes between self and
due to a cluster of species-specic residues nonself peptides. While peptide presentation
present near the peptide-binding region (16) by Qa-1 and HLA-E plays a key role in innate
that constitutes part of the CD94/NKG2- immunity, their dual ability to present peptides
binding site as revealed in the HLA-E/ to T cells suggests a complicated coevolution
CD94/NKG2A complex crystal structures with these two very different receptor systems.
(6, 7). The footprint of the CD94/NKG2A
receptor on HLA-E spans the peptide-binding

groove, with the CD94 and NKG2A subunits HLA-G and Qa-2
binding almost exclusively to the 1- and 2- Similar in overall structure to HLA-E and
helices, respectively (Figure 4a, right panel ). Qa-1 are HLA-G and Qa-2 (Figure 4b). Both
This positions the receptor over the P5, P6, are expressed in various forms (membrane-
and P8 positions of the peptide and explains the bound and soluble isoforms) as a result of
extreme sensitivity of CD94/NKG2 binding alternative mRNA splicing. HLA-G is also
to subtle changes in peptide conformation at a ligand for inhibitory receptors expressed
these positions (reviewed in 24). on NK cells; its primary immune function
In addition to their roles in innate immunity, is more specialized, however. HLA-G is
both Qa-1 and HLA-E are capable of eliciting predominantly expressed on fetal extravil-
a specic CD8+ T cell response to a variety lous trophoblasts, providing signals to NK
of pathogens such as Salmonella typhi, Mycobac- cells, macrophages, and monocytes through
terium tuberculosis, and cytomegalovirus (CMV) leukocyte immunoglobulin-like receptor-1
(reviewed in 25). The peptides characterized (LILRB1, LIR-1, or ILT-2), LILRB2 (LIR-2
from these responses can differ markedly in se- or ILT-4) (26), and killer immunoglobulin-like
quence from the canonical leader peptide se- receptor 2DL4 (KIR2DL4) (27, 28) that help to
quence or can be highly similar, such as with the maintain maternal tolerance and promote fetal
human CMV UL40 peptide. The UL40 pep- development. Encoded by the ped gene (preim-
tide mimics endogenous leader sequences (it is plantation embryonic development), the Q9
identical in sequence to some HLA leader se- antigen of the Qa-2 family of proteins (referred
quences) to maintain HLA-E expression on the to as Qa-2 here) was also recognized early
cell surface and circumvent CD94/NKG2 de-
tection of downregulated classical class I. This
peptide can elicit a strong CD8+ T cell response LEUKOCYTE IMMUNOGLOBULIN-LIKE
in individuals lacking the identical endogenous RECEPTOR
leader sequence because these T cells have es-
caped negative selection. They can go on to LILRs are also known by the names CD85, ILTs, and LIRs. They
make up a signicant proportion of the CD8+ contain immunoglobulin domains and are similar in overall ter-
T cell memory pool in some immune individ- tiary structure with the KIRs (killer immunoglobulin-like recep-
uals (5). The complex crystal structure of an tors). LILRs are expressed by immune cell types of both myeloid
TCR reactive to HLA-E/UL40 peptide (5) and lymphoid lineage and can have broad immunomodulatory ef-
provided the molecular basis for this interac- fects on many different immune cells. Classical and nonclassical
tion. The docking of the TCR was strikingly MHC molecules can be ligands for a subset of LILRs; as discussed
similar to that seen in recognition of classical in the text, some of these (LILRB1 and LILRB2) recognize 2 m-
MHC and overlapped with the binding site for associated MHC molecules, whereas some activating LILRs have
CD94/NKG2A (Figure 4a, right panel ); how- a preference for 2 m-free MHC heavy chains.
ever, the bulk of the interaction centered on

as playing a role in embryonic development. disulde-linked dimer in solution and on the

Detection of Qa-2 transcripts in embryos impli- cell surface (11, 37). The HLA-G disulde
cates this molecule in reproductive tolerance in linked conformation enhances interaction
the mouse as well (19), although its interaction with LILRB1 (11, 38) yet would likely inhibit
with specic receptors has not been demon- KIR2DL4 binding, which is thought to be
strated. Both HLA-G and Qa-2 have also been similar to that of KIR recognition of classical
implicated in tumor surveillance via peptide MHC (39). The regulation of this form of
presentation to CD8+ T cells (reviewed in 29). HLA-G may therefore play an important
Peptide presentation by HLA-G (30) and role in immune modulation, as it can serve to
Qa-2 (3133) is more promiscuous than that engage one set of receptors over another.
by HLA-E and Qa-1, although the repertoire

of available peptides may be more restricted in
tissues that express these proteins, as is the case M3: Specialized for N-Formyl Peptide
Presentation
with HLA-G expression in the placenta (34).

In contrast to the highly conserved grooves of Antigen presentation by the rodent M3
HLA-E and Qa-1, the peptide-binding grooves molecule (Figure 5) is specialized for bacterial
of HLA-G and Qa-2 differ despite overall peptides, using a fundamental difference
highly similar main-chain conformations of in prokaryotic (and mitochondrial) protein
their platform domains (Figure 4b, upper panel ) synthesis as its target. Protein translation
(12, 17). HLA-G peptides have preferences initiation in bacteria and mitochondria uses
at three positions: Pro or small hydrophobic N-formylmethionine rather than amino-
residue at position 3, Pro or Gly at position 4, methionine used in eukaryotic protein
and Leu at the C terminus (P9). Peptide anchors translation. M3s groove has evolved to have
for Qa-2 are shifted slightly, with preferences an exquisite selectivity for this protein modi-
at P2 (Met, Leu, and Gln), P3 (Asn, Iln, and cation, with a nearly 10,000-fold preference
Leu), P7 (His), and P9 (Leu, Iln, and Phe). The for N-formyl peptides over nonformylated
overall conformation of the peptides in HLA- peptides (40, 41). The crystal structure of M3
G and Qa-2 are most similar at their N and C revealed a groove lined with predominantly hy-
termini; the central peptide positions of HLA- drophobic residues, narrow at the N-terminal
G exhibit more conformational exibility (14), end and wider and deeper at the C-terminal
consistent with their differences with the Qa-2 end (Figure 5). The specicity for N-formyl
peptide conformation. Analysis of the thermal peptides is derived from the specic shape and
stability of HLA-G bound with four different chemistry of the B pocket (the A pocket is
peptides (14) revealed the relationship between occluded), where a histidine at position 8 (H8)
HLA-G stability and peptide specicity, which lining the bottom of the B pocket forms a hy-
correlates with the important effect of the avail- drogen bond directly with the carbonyl oxygen
able peptide pool to HLA-G expression (35). of the formyl group, which would be lacking in
The complex structure between HLA-G nonformylated peptides (Figure 5, right panel ).
and LILRB2 (LIR2) (13) (Figure 4b, lower In addition, H8s interaction with neighboring
panel ) provided a molecular model by which aromatic residues was hypothesized as pro-
to understand how HLA-G engagement by viding stability when H8 is in a protonated
LILRB2 differs from HLA-A2 engagement state, disfavoring the binding of nonformylated
of LILRB1 (36). Although the binding sites peptides that would carry a positively charged
overlap and are focused on the 2 m and 3 N terminus. The peptide is stabilized by addi-
domain interface, LILRB2 is more 3-domain tional contacts, primarily with residues P1P4.
focused, allowing for 2 m-independent recog- These stabilizing contacts are also reected in
nition of HLA-G as well as other classical the conformation of the peptide in M3s groove:
class I molecules (13). HLA-G can exist as a The rst four residues of the peptide are buried
536 Adams Luoma

O N-formylmethionine
M3 H
S OH
H3C
1 HN H
O
fMTF 1
P2
P4
P3
P1
2
H8
Figure 5
N-formyl peptide presentation by the rodent M3 molecule. (Left) M3 (PDB ID: 1MHC) is shown as a ribbon and semitransparent
surface in pale green, showing the modied peptide-binding groove adapted for presentation of N-formylated peptides [the formylated
MTF peptide (fMTF) is shown as sticks in white]. (Right) Magnied view of the fMTF peptide (white stick) bound in the M3 groove;
residues important in peptide anchoring through the N-formyl group are shown as pale green sticks. A chemical diagram of
N-formylmethionine is shown, indicating the chemistry of the formyl group.
deep within the groove, with the remaining ve interaction with M3; there do not appear to be
extending up and out toward solvent (Figure 5). restrictions on the V or V domains used in
There does not appear to be a length re- the M3-restricted repertoire; therefore, this in-
quirement for M3-restricted peptides (42), teraction may be similar to the interactions ob-
suggesting that the C terminus of the peptide served for classical and some TCR-restricted
continues to extend out of the M3 groove. nonclassical (see previous discussion of HLA-
A polyclonal CD8+ T cell response re- E) complexes. The potential promiscuity of the
stricted to M3 can aid in the protection against peptide C terminus and its exibility outside of
infection with mycobacterial species such as Lis- the M3 groove (15) would suggest that docking
teria monocytogenes or Mycobacterium tuberculosis of the TCR would focus more on the stable N
(reviewed in 25). These M3-restricted T cell terminus of the peptide, bound centrally in the
responses occur more rapidly than responses M3 groove (Figure 5).
restricted to classical MHC, and investigators
(43) have suggested that M3-restricted T cells
exist in a memory state owing to persistent in- THE SPECIALIZED MHC
teraction with cross-reactive antigens derived HOMOLOGS I: T AND M
from commensal bacteria. The lack of this rapid LINEAGE PROTEINS
M3-restricted response in specic pathogen Outside of the evolutionary grouping of the
free (SPF) mice supports this hypothesis (43, peptide-presenting MHC molecules are MHC
44). Selection of these M3-restricted T cells oc- proteins that have modied MHC scaffolds Specific
curs in the thymus; however, both the source of adapted for divergent functions. The highly pathogenfree (SPF):
the selecting peptides and the similarity of these diversied T and M proteins found in the used to describe mice
that are guaranteed to
selecting peptides to their antigenic epitopes mouse do not have clear orthologs or even
be free of specied
are unclear (reviewed in 2). Currently, there is homologs in humans and thus are thought to pathogens
no information at the molecular level on TCR have become specialized for murine-specic

functions. These molecules retain the basic the CD8 receptor on activated CD8+
MHC class I fold and require 2 m for stable T cells is a key step in memory development
Antigen-presenting expression, yet they have modied their folds and also provides a selective checkpoint, as
cells (APCs): cells away from classical peptide presentation, CD8+ T cells lacking CD8 expression
that have the capability instead adapting it for highly specialized are killed by TL engagement (46). The crystal
of presenting antigens,
functions. structure of TL in complex with CD8 (51)
usually via MHC
molecules on their cell revealed that TL has a closed binding groove
surface
TL and T10/T22 that is due to the inward shifts of both the
The T and M lineages found in mouse (Fig- 1- and 2-helices, approximately 7 A closer
ures 1 and 2) have many related MHC-like than that of typical peptide-presenting grooves
molecules with currently undened functions. (Figure 6a). Instead of antigen presentation,
Exceptions to these are TL (thymus leukemia TL appears to have evolved an optimized
antigen, encoded by the T3 and T18 genes), the interaction with CD8. Although similar
T10/T22 proteins (in the past referred to as in footprint to those observed in classical
TL-antigens), and M10. No homologs of these MHC/CD8 interactions where the 3
lineages have been found in humans, which domain is targeted (Figure 6a, bottom), TLs
suggests that their diversication has been interaction with CD8 has more hydropho-
limited to the rodent lineage. Despite sharing bic and hydrogen bonding contacts, resulting
the MHC fold, TL and T10/T22 interact in a reinforced interface (51).
very differently with T cells; TL binds to the T10 and T22 are currently the best-
CD8 homodimer ten times more strongly described ligands for T cells; their interac-
than to CD8 (45) and can modulate T tion with these T cells has been well described
cell reactivity and memory (46), whereas T10 functionally (reviewed in 47) and at the molecu-
and T22 interact directly with TCRs expressed lar level (52, 53). Additionally, T22 is expressed
on a particular population of T cells in the in neurons and is thought to play a role in neu-
mouse (47). TL has restricted expression, found ronal plasticity (reviewed in 54). T10 and T22
on intestinal epithelial cells and immature thy- are highly homologous, sharing 94% amino
mocytes (48, 49), and can be upregulated on acid identity, and are expressed in many differ-
antigen-presenting cells (APCs) such as den- ent tissues and cell types in the mouse. They
dritic cells (DCs) (50). TLs interaction with differ from classical MHC molecules in that
their antigen-binding groove has been exten-
sively modied, including a severe inward tilt
T CELLS of the 1-helix and disruption of the 2-helix,
which is partially unraveled and thus exposes
T cells are the second T cell lineage that expresses a TCR com- the -sheet of the platform domain to solvent
posed of a and chain in lieu of and chains, as in T cells. (55) (Figure 6b). Both structural and biochem-
These cells predominate in the peripherymostly in epithelial ical approaches suggest that these molecules do
tissueswhere they survey for stress, infection, and tumorigen- not function to present antigen, but instead are
esis. These cells typically have an activated phenotype and there- recognized directly by reactive T cells. Al-
fore can respond quickly and potently to activating stimuli. T though it remains unclear what immune func-
cells are not restricted to classical MHC molecules; instead, they tion these T cells perform, there is a clear bias
recognize diverse antigens, many of which remain uncharacter- in cytokine secretion dependent upon T22 ex-
ized. T10/T22, as discussed in the text, are the best-characterized posure during development. T10/T22 reactive
ligands for T cells. Extensive efforts are under way to better T cells that develop in a T22-positive envi-
dene the ligands for this T cell lineage in human and in mouse, ronment secrete IFN- after ligand exposure,
to better understand their functions, and to establish means to whereas naive T cells (those that develop in
manipulate them in human health. a T10/T22-negative environment) upon ligand
engagement secrete IL-17 (56).
538 Adams Luoma

a TL HLA-A2 b T22 HLA-A2 c M10 HLA-A2
1
1 1 G8
2
2
2
CDR3
2
1
1 1
CD8 T22
CDR3
1
Y L dEV8 2
2
2m
2m 2
3 W
Figure 6
Structural adaptations by the T and M lineage proteins in mouse. (a) Top: superposition of the TL antigen (PDB ID: 1NEZ) and
HLA-A2 (PDB ID: 1DUZ) shown in yellow and white ribbon, respectively. Bottom: TL shown from the side in yellow ribbon, 2 m
shown in orange. In complex with TL is CD8, shown as green ribbon, which binds TL predominantly via its 3 domain. (b) Top:
comparison of T22 (hot pink ribbon, PDB ID: 1YPZ) with HLA-A2 (white ribbon). Right column: complex of the G8 TCR with T22
(PDB ID: 1YPZ); G8 is shown in pale green ( chain) and pale cyan ( chain) with the CDR3 loop indicated by the dashed box. Inset:
surface representation of the T22 surface (hot pink) with a comparison of the G8 CDR3 loop (cyan and pink) and its anchor residues
(W, Y, and L) with that of a peptide (dEV8, shown in yellow cartoon tube and sticks) from the classical class I molecule H2-Kb . Alignment
was performed on the heavy chains of T22 and Kb ; the positions of the peptides are derived from this alignment. The key W of the
CDR3 loop is shown as sticks and dots. (c) Top: structural alignment of M10 (blue ribbon, PDB ID: 1ZS8) with HLA-A2 (white).
Bottom: surface representation of M10 with its binding groove colored in light blue, for perspective.
Approximately 0.12% of murine T cells M afnity, has a histidine in this interface,

recognize T10/T22 and do so in a way unlike whereas the allelic variants, T10b and T22b,
that of other T cell recognition strategies. Bind- have prolines and are bound by G8 with a 10-
ing of T22 by the TCR is mediated almost fold higher afnity. Mutagenesis of the residues
exclusively by the CDR3 loop (Figure 6b) within the CDR3 loops of T10/T22 reactive
(52, 53), with little contact from the remaining TCRs has revealed the energetically important
CDR loops of the TCR. Within this loop is a residues of the loop. Of the W. . .EGYEL mo-
motif found in all T10/T22-reactive TCRs tif, the W was found to be required for binding,
(57): a W followed by an EGYEL motif. The and the Y and L were the second and third most
number and chemical makeup of the amino important residues for binding in all but one of
acid residues between the W and EGYEL can the loops examined (53, 58). Close examination
vary and modulate the afnity of the TCR for of the positioning of the Y and L residues of
T10/T22 (57, 58). Furthermore, allelic variants the CDR3 loop on the T22 surface reveals
of T10 can also modulate T cell reactivity an interesting homology to that of peptide
through a polymorphism at position 124 lo- presentation by classical MHC molecules; an-
cated at the edge of the -sheet, directly in the chor residues (of strikingly similar chemistry)
binding interface (53). T10d, which binds the in classically presented peptides are found in
G8 TCR (one of the earliest TCRs char- similar positions (Figure 6b). Furthermore,
acterized to respond to T10/T22) with 900 the required CDR3 loop W is positioned in

a way to complete the groove in T22, mim- those MHC-related proteins that have clear
icking peptide presentation by classical class orthologs between divergent species such as
I molecules. This suggests that T10 and T22 mouse and human. These proteins can have
have retained some of the peptide-presenting both immune and nonimmune functions and
features of their classical relatives, and these in some cases appear to serve both, although
TCRs use these features to engage T10/T22 it is unclear whether their dual functionality is
directly, in a peptide-like fashion (58). linked.
M10: A Pheromone Detector?

ZAG: An MHC Fold Adapted for
M10 represents one of the more interesting Lipid Metabolism

cases of the diversied role of MHC molecules
ZAG (zinc-2-glycoprotein) is an excellent ex-
in rodents. M10 molecules associate with 2 m
ample of MHC scaffolds modied specically
and bind to (and are required for the expres-
for nonimmune functions. It is expressed as a

sion of) a family of G proteincoupled receptors
soluble heavy chain independent of 2 m and
called V2R (reviewed in 3); these are expressed
is found at high concentrations in serum and
in the vomeronasal organ and are thus referred
other bodily uids (60). ZAG stimulates lipid
to as vomeronasal receptors. The vomeronasal
breakdown in adipocytes, contributes to the re-
organ is one of the key detectors of pheromonal
duction of fat stores in animal models (61), and
cues that regulate sexual and social interactions
has been linked to the fat-depletion effect of
between individuals and can also control hor-
cachexia (62), a wasting phenomenon present
monal release. The structure of M10 (59) re-
in many patients with cancer, AIDS, and other
vealed an MHC fold similar to that of classi-
life-threatening diseases. The structure of ZAG
cal class I molecules with an open (yet empty)
is highly similar in backbone conformation to
groove suitable for binding small peptides or a
classical class I molecules (Figure 7a, top) de-
peptide chain (Figure 6c). How M10 associates
spite sharing only 3040% amino acid identity
with the V2R receptors is unknown; however,
(63), with modications to the putative antigen-
the open nature of one end of M10s 1 and 2
binding groove that would likely prevent pep-
groove may be a suitable association site (59).
tide presentation. Instead, ZAGs groove is
Although the exact role of M10 in pheromone
well adapted to binding small, hydrophobic
detection is unclear, M10 may function as both
molecules similar in structure to polyethylene
a chaperone and coreceptor for the V2R recep-
glycols (PEGs) (Figure 7a, bottom) or fatty acids
tors, helping to modulate the receptor speci-
(64), although the identity of the physiologi-
city of pheromonal cues (reviewed in 3). The
cally relevant ligand remains unknown. Muta-
diversication of the T and M lineages in the
genesis of the binding groove revealed an im-
mouse has generated many variations on the
portant role for R73, which is the only charged
MHC scaffold that could be used for many dif-
residue located in the hydrophobic binding
ferent immune and nonimmune functions. Def-
groove lined with aromatic residues. This
inition of the functions of these molecules will
charged residue extends into the groove from
provide further examples of how the MHC fold
the 1-helix and stabilizes the grooves open
can be adapted rapidly (in evolutionary time) for
state, as mutation to alanine abrogates binding
new functions.
of ligand and closes the groove to solvent (65).
The residues lining the groove are identical
THE SPECIALIZED MHC in ZAG mammalian homologs (65), suggesting
HOMOLOGS II: ZAG, HFE, AND that ZAG ligands are highly conserved between
FcRn these species. There is evidence that ZAG binds
In contrast to the rapid diversication of MHC directly to the -adrenoreceptors 2 (2-AR)
scaffolds in the T and M lineages, there are and 3 (3-AR), but not 1-AR; this binding
540 Adams Luoma

correlates with increases in cyclic AMP (66), where the cycle begins again. HFEs association
providing a potential link between ZAG expres- with the TfR is not a competition but rather
sion and lipolysis. ZAG does not appear to be functions for ne-sensing of the available
involved in immune defense, as ZAG knockout iron stores and may modulate the level of the
mice have no clear immunodeciencies (67) and secreted iron-regulatory hormone hepcidin
there are no reports of T cells that bind to or (reviewed in 74). Although most of the initial
are restricted by ZAG. studies focused on HFE have dismissed a role
for this molecule in the immune system, more
recent studies have shown that HFE-reactive
HFE: An MHC Fold with a Role in T cells do exist (75, 76) and that deletion of
Iron Uptake HFE in the mouse results in a decrease in the

The human hemochromatosis protein, or number of T cells expressing V6 domain
HFE, was discovered owing to its genetic link TCRs (75). HFE therefore retains a topology
with an iron storage disorder called hereditary suitable for TCR binding, and its involvement
hemochromatosis (68). Mutations in HFE are in selection of the T cell repertoire suggests
common in individuals of Northern European this is not a spurious reactivity.
descent, segregating at a 1012.5% frequency
in this population and resulting in 0.250.5%
of individuals affected (69). The common FcRn: An Antibody Fc Receptor
mutations in HFE, for example Cys260Tyr with an MHC Fold
(which disrupts HFEs association with 2 m), The neonatal Fc receptor (FcRn) is another
result in excessive iron deposition in tissues and MHC-like molecule (77) that has been adapted
organs, and this is thought to be due to HFEs to purposes other than antigen presentation.
ability to regulate iron uptake by transferrin Much of the work on FcRn has focused on its
(Tf) by associating with the Tf receptor (TfR) function in passive immunity; its initial charac-
(70, 71). Unlike other ligand-presenting class terization was in the intestinal epithelial cells
Ilike molecules, HFEs binding groove is of neonatal rodents, where it captures IgG
closed due to a 4-A translation of the 1-helix molecules from maternal milk and transports
closer to the 2-helix and substitutions of them across the mucosal layer, releasing them
larger side chains at positions lining the groove into the blood (77, 78). FcRn is now known to
(Figure 7b) (72). HFE has not been shown be expressed at all life stages, and in humans it is
to present or associate with ligands (including additionally found to be expressed in tissues in-
iron), although its association with the TfR cluding the lung, liver, and placenta. Most cells
has been well studied biophysically (72) and of hematopoietic origin in mouse and human
structurally (Figure 7b, bottom) (73). TfR binds express FcRn (reviewed in 79, 80). In addition to
HFE on the platform domain, with most of the its role in passive immunity transcytosis, FcRn
contacts centered on the 1-helix (73). Like is involved in maintaining circulating IgG lev-
Tf s association with TfR, HFE associates with els and regulating mucosal and systemic immu-
TfR with a pH dependency. At pH 7.5, which nity (8183). Like other MHC-like molecules
corresponds to the pH of the extracellular that have evolved away from antigen presenta-
space, HFE and iron-bound Tf (Fe-Tf) bind tion, FcRns groove is closed (Figure 7c) (84)
TfR tightly with KD s of 0.6 M and 5 M, and does not function in Fc binding (85). In-
respectively. Upon endocytosis and trafcking stead, FcRn binds to one Fc chain via the edge
to the endosome, the low pH environment of its platform domain, with residues from the
causes iron and HFE dissociation; the iron is 2 domain and 2 m subunit making the major-
made available for further processing for cellu- ity of contacts (Figure 7c, bottom) (86). Key to
lar metabolic needs, whereas holo-Tf bound to FcRns function is its pH dependence for bind-
TfR and HFE are recycled to the cell surface, ing. In contrast to HFE, FcRn binds tightly to

FcRn HLA-A2
HFE HLA-A2
a ZAG HLA-A2/HTLV-Tax b c
1 1
1
2 2
2
2
Ig-Fc
R73 1 1
+ H436
D137
1
2 H435
2 E132 +
PEG
2m
+ H310
TfR 3
E117
Figure 7
MHC structures specialized for functions other than antigen presentation. (a) Top: ribbon diagram of zinc-2-glycoprotein (ZAG;
blue, PDB ID: 1T7V) compared with that of HLA-A2 (white, PDB ID: 1DUZ). The side perspective, to the left, shows ZAG, lacking
2 m, compared with 2 m-associated HLA-A2. In the top perspective, to the right, the platform domains of ZAG and HLA-A are
depicted, including the HLA-A peptide (HTLV-Tax). Bottom panel: surface representation of the ZAG-binding groove represented in
transparent surface and ribbon. R73, determined to maintain the conformation of the ZAG-binding groove and to be required for
ligand binding, is shown in dark blue. A polyethylene glycol (PEG) found bound in the groove is shown as yellow spheres, oxygen
shown in red. (b) Top: structure of human hemochromatosis protein (HFE; plum ribbon, PDB ID: 1A6Z) compared with that of
HLA-A2 (white ribbon). Bottom: transparent surface representation of the platform domain of HFE in light plum, with the binding
footprint of the transferrin receptor (TfR) (PDB ID: 1DE4) shown in hot pink. TfR binds to HFE via the platform domain similar to
how many immune receptors recognize their MHC ligands. (c) Top: ribbon diagram of the neonatal Fc receptor (FcRn) shown in green
(PDB ID: 1T1A) compared with that of HLA-A2 (white ribbon). Bottom: FcRn shown from the side, with the binding site for the
antibody Fc shown in yellow-orange and in a surface representation (PDB ID: 1TLA). Inset shows the pH-dependent histidines of the
Fc molecule ( yellow-orange) and how they form salt bridges when protonated (at low pH) with FcRn.
its target at low pH and dissociates at the more cargo from one compartment to another with-
basic, extracellular pH of 7.4; this is important out the requirement for protein conformational
for binding of target IgG in the intestinal lumen change.
and in the endocytic pathway and for its appro-
priate release upon exposure to the more basic
environments of the extracellular space such as The Human MIC Proteins
the blood. Four key salt bridges form the core of The human MICA and MICB (MHC class
the binding interface between FcRn and Fc, and I chainrelated A and B) proteins are 2 m-
three of these involve histidines contributed by independent MHC-like proteins that are found
Fc (Fc H310/FcRn E117, Fc H435/FcRn E132, in many other mammalian species (reviewed
and Fc H436/FcRn D137) (Figure 7c, bottom). in 87) but are absent in mouse, suggesting that
Protonation of these histidines at low pH al- they were deleted in the rodent lineage. MICA
lows salt-bridge formation; deprotonation and and MICB are ligands for the NKG2D receptor
subsequent salt-bridge disruption occur when and are therefore discussed further in the sec-
the pH increases, an elegant way to transfer tion focused on NKG2D MHC-like ligands,
542 Adams Luoma

below. Phylogenetically related homologs microbial-derived lipids, it is understandable

termed MILL (MHC class Ilike located near that the immune system evolved a mecha-
the leukocyte receptor complex; see Figure 2) nism to subject this repertoire to immune
do exist in the mouse; MILL1 and MILL2, in surveillance.
contrast to MICA and MICB, associate with
2 m and are not ligands for NKG2D. There is
some indication that MILL2 may play a role in CD1 Expression, Trafficking, and
metabolism and wound healing (88); however, Lipid Repertoire
the details of this interaction, the function The Group 1 CD1 molecules are predomi-
of the MILL proteins as a whole, and their nantly expressed on DCs and on developing
structures need further elucidation. thymocytes (97). In particular, Langerhans

DCs in the skin highly express the CD1c and
CD1a isoforms. In contrast, CD1d has a more
THE LIPID-PRESENTING MHC
widespread expression pattern, with most B

MOLECULES: CD1 AND EPCR cells expressing CD1d, as do several non-
The CD1 family of antigen-presenting hematopoietic cell types. Intestinal epithelial
molecules is one of the most well studied cells in particular have high CD1d levels in
among MHC-like molecules (reviewed in 89, mice and humans (97). Although the unique
90). In humans, there are ve isoforms, termed structural features of CD1 family members
CD1ae, whereas mice and rats express only allow for presentation of a diverse array of self,
CD1d. These isoforms have been classied microbial, and environmental lipids, lipid pre-
into three groups based on sequence similari- sentation by each CD1 molecule is dependent
ties: CD1ac form Group 1, CD1d comprises on its exposure to ligand. Hence, a distinct
Group 2, and CD1e comprises Group 3. It is hy- feature of the CD1 family is the different
pothesized that CD1 evolved from duplication intracellular trafcking pathways of the family
of the MHC class I locus in a primordial rep- members, through which they can encounter
tilian ancestor, as sh have no evidence of CD1 and bind self and nonself lipids localized to
genes. The CD1 locus later underwent translo- those compartments (reviewed in 98100). All
cation to chromosome 1 and 3 in primates and isoforms except for CD1e trafc to the cell
rodents, respectively (91). Seminal work in the surface after synthesis in the endoplasmic retic-
late 1980s and early 1990s determined that ulum and are subsequently internalized and
CD1 can be recognized by and present micro- directed to different endosomal compartments.
bial antigens to T cells (92, 93), antigens that CD1 molecules can then exchange self lipids
were later found to be lipidic in nature, estab- in the endosomal system with stimulatory self
lishing a new paradigm for T cell antigen recog- and microbial lipids (reviewed in 101).
nition (94). Insight into how CD1 molecules The Group 1 CD1 molecules have a par-
could bind and present lipid antigens was ticular importance in the presentation of my-
gleaned from the crystal structure of murine cobacterial lipids. The rst described was my-
CD1d, which revealed two large hydrophobic colic acid, a long chain (C70C90) lipid from
pockets that could bury the lipid tails, exposing M. tuberculosis that can be presented by CD1b
the polar head group of the antigens outward molecules to T cells (94). Subsequent stud-
from the binding groove (95). Another key de- ies identied other mycobacterial ligands that
velopment of the early CD1 story was the iden- are presented to T cells by CD1b, including
tication of an NK1.1+ T cell population the PIMs (phosphatidylinositol mannosides),
with a restricted TCR repertoire that rapidly LAMs (lipoarabinomannans), GMM (glucose
produces IL-4 and IFN- upon CD1d-antigen monomycolate), and diacylated sulfoglycolipids
recognition, called natural killer T (NKT) cells (Figure 8) (reviewed in 101). GMM is similar
(96). Given the tremendous diversity of self and to mycolic acid with its long acyl chain, whereas

a CD1a-presented lipids b CD1b-presented lipids

O O O
H Diacylated
N N NH sulfoglycolipid Mycolic acid
O N
H (mycobacteria) (mycobacteria)
OH O O Didehydroxy-
N-aryl branch Lysine branch mycobactin
(mycobacteria) OH OH
2-sulfate-trehalose
C20:1 fatty acid O OH
HN O
HO
HO
O
SO4 O
O OH
OH C18:0 fatty acid O
OH O OH
HN O O
O
O
O O
O 3S OH Sphingosine
OH
3 Sulfogalactose Sulfatide (self)
C16:0
fatty acid
c CD1d-presented lipids -Galacto-

sylceramide
(marine sponge)
HO OH O C26:0 fatty acid
O
HO HN OH
OH
O
Galactose
OH Phytosphingosine
-Galacturono-
sylceramide OH
HO OH
(Sphingomonas)
O O
O C14:0 fatty acid Hydroxy-
HO HN
phthioceranic
OH acid
Galacturonic O
acid Dihydrosphingosine
OH
OH
Mannosyl-1-phosphomycoketide (mycobacteria)
HO C32 isoprenoid
O
HO O
HO O
P
Mannose O O
NH2 NH2
12-mer peptide
NH GGKWSKXSKWSK NH
OH
O O O O O O
H H H H H H
N N N N N N N N N N N N OH
O H H H H H H
O O O O O O
OH O OH
Lipo-12 NH2
NH2 (synthetic) NH2
C18:0 fa
tty acid
d CD1c-presented lipids
544 Adams Luoma

the PIMs, LAMs, and sulfoglycolipids have two void by responding to other lipidic cell wall
shorter acyl chains and a head group contain- components.
ing two or more sugars. The diverse structures
of these lipids show that there are multiple CD1 Structures: MHC Folds Adapted
ways to ll the network hydrophobic tunnels of to Binding Diverse Lipid Molecules
CD1b, the structure of which is discussed be- More than a decade after the rst structure of a
low. CD1a and CD1c present structurally dis- CD1 molecule was determined, the structures
tinct mycobacteria-derived lipids to T cells that of all ve CD1 isoforms have now been solved.
include lipopeptides and isoprenoid glycolipids CD1ad present a diverse array of lipid antigens
(Figure 8) (102, 103). Together, the acyl chains
for T cell recognition, as discussed above, and

that can be accommodated in the Group 1 CD1 a comparison of the antigen-binding grooves
antigenbinding grooves range in size from among these molecules (Figure 9) reveals a
18 to 80 carbons in length, with head groups mechanism by which this diversity is possible.
ranging from a single phosphate to 12 amino The volumes of the hydrophobic pockets of
acids, making an extensive array of mycobacte- Group 1 CD1 molecules range from 1,300 A3
rial lipids amenable to T cell recognition. for CD1a to 2,200 A3 for CD1b and correlate
The canonical nonself ligand for CD1d, to the numbers of tunnels in these molecules,
the glycosphingolipid -galactosylceramide which range from two to four, respectively. In
(GalCer), was derived from a marine sponge the rst structure of murine CD1d, the authors
and identied in a screen for anticancer ther-
apeutics (104). It was then subsequently found
to exert its pharmacological effect by activating LIPID LOADING INTO CD1 MOLECULES
NKT cells in a CD1d-dependent manner
(105). Though GalCer is not encountered An important topic in CD1-mediated lipid presentation is the
during bacterial infections in mice or humans, mechanism of lipid loading, which involves extraction of lipids
it has been instrumental in dening the func- from membranes and often requires additional lipid-binding pro-
tions of NKT cells (reviewed in 89). Searches teins. Saposins AD are a family of lipid transfer proteins that
for microbial ligands that CD1d could present directly transfer lipids into CD1d and, in turn, are important
in the context of a physiological infection for presentation of exogenous and endogenous antigens to NKT
identied glycolipids from the cell walls of cells. CD1e also facilitates loading of other CD1 molecules; re-
Sphingomonas and Borrelia burgdorferi, which cent studies showed that CD1e is more efcient than saposins at
share the -anomeric sugar linkage of GalCer enhancing GalCer responses by NKT cells and also facilitates
(Figure 8) (106108). As these bacteria do not CD1b- and CD1c-restricted responses. This activity was medi-
contain the potent TLR agonist lipopolysac- ated by directly facilitating the loading and unloading of lipid
charide, NKT cells may have evolved to ll this antigens on CD1 molecules (reviewed in 101).

Figure 8
Structures of representative lipids presented by CD1ad molecules. (a) CD1a-presented lipids. Shown are mycobacteria-derived
didehydroxymycobactin and the self lipid 18:0 sulfatide crystallized in the rst CD1a structure. The length of chains that can be
accommodated by CD1a is 1820 carbons maximum. (b) CD1b-presented lipids. Shown are mycobacteria-derived mycolic acid and
diacylated sulfoglycolipids. CD1b can accommodate very long chain lipids owing to the presence of a connected pocket architecture
and an exit portal under the 2-helix. Lipid modications such as methyl branches and cyclopropyl groups can also be accommodated
in the CD1b-binding groove. (c) CD1d-presented lipids. The potent iNKT cell agonist -galactosylceramide and
Sphingomonas-derived -galacturonosylceramide are shown. The diversity of head groups that can be accommodated by CD1d is more
restrictive than for other CD1 molecules owing to the smaller size of the main portal. (d ) CD1c-presented lipids. Shown are the
mycobacteria-derived mannosyl-1-phosphomycoketide and the synthetic Lipo-12. The open nature of the CD1c-binding groove
could facilitate presentation of 12-mer peptides. See Mori & Di Libero (101) for lipid references.

identied two hydrophobic pockets, termed the CD1 structures. In all structures solved to date,
A and F pockets based on their relation to burying of the hydrocarbon chains in the hy-
the AF pockets of MHC class I molecules drophobic antigen-binding pocket places the
(95). This nomenclature has been used to de- polar head group between the 1- and 2-
scribe the ligand-binding pockets of subsequent helices for potential TCR recognition.
The CD1a structure in complex with the self
CD1a: sulfatide Pocket lipid sulfatide reveals a narrow semicircular A
pocket, with a dened terminus that restricts
the length of alkyl chains that can be accom-
A modated, and thus is described as a molecular
F 1
F ruler (Figure 9) (109). The F pocket is straight

A
and widens toward the surface of the antigen-
2
binding cavity, potentially allowing more vari-
ability in ligand structures that occupy this

CD1b: GMM space. The subsequent structure of CD1a in
complex with mycobacterial lipopeptide reveals
F the accommodating nature of the F pocket,
T
given that the lipopeptide head group traces a
A C 1
similar path within this pocket, as does the sul-
A F
fatide fatty acyl chain (110).
T
2 The extensive pocket volume of CD1b
C portal explains its ability to present the long chain
mycolic acids and glucose monomycolates
CD1c: MPM, c12 spacer (Figure 9). The rst structures were solved
D/E portal
A F 1
Figure 9
A F Comparison of lipid binding and pocket structures
2 of the ve CD1 isoforms. (Left) The CD1a-sulfatide
is depicted in light orange (1ONQ), CD1b-glucose
monomycolate (GMM) in pale cyan (1UQS),
CD1c-mannosyl-1-phosphomycoketide (MPM) in
CD1d: GalCer light pink (3OV6), CD1d--galactosylceramide
(GalCer) (1ZT4) in light purple. The CD1d
2-helix has been removed for clarity. The polar
lipid head groups protrude from the binding groove
F between the -helices, available for TCR
A 1
F recognition. The lipid lengths that are
A accommodated by CD1 molecules range from 36
2 carbons (CD1a) to 60 carbons (CD1b). (Right)
Pocket architecture of CD1 molecules. All
molecules have hydrophobic pockets designated A
and F , although length and width vary. CD1b and
CD1c have additional portals exiting under the
CD1e: empty
-helices that allow for additional accommodation
of long lipid tails. The central portal sizes also vary,
1 with CD1d having the smallest in area, as the roofs
F of the A and F pockets are closed off. CD1c and
A
CD1e have a more open pocket architecture,
2 allowing for accommodation of diverse lipid head
groups.
546 Adams Luoma

with the self lipids phosphatidylinositol and the phatidylcholine (LPC) (115) revealed a shifted
ganglioside GM2, revealing four lipid-binding 1-helix resulting in an open A pocket, sug-
tunnels (111). The positions of channels A and gesting that the core structure of CD1d is exi-
F correspond to those in the CD1d structure, ble, possibly a feature required for efcient lipid
but an additional central C channel and a loading. The conformation of the CD1d/LPC
T tunnel connect these pockets, signicantly structure was strikingly similar to the structure
expanding the overall pocket volume. The C of an empty CD1d also noted in the original
pocket terminates via a solvent-exposed exit human CD1d structure paper (116).
portal under the 2-helix, where potentially The recently solved structure of CD1e cor-
long alkyl chains could exit if not completely relates with its ability to facilitate lipid exchange
accommodated within the internal binding with other CD1 molecules (117). CD1e has the
pockets. Modeling of the CD1b structure in widest binding groove among CD1 molecules
complex with mycolic acid, and later crystal- (Figure 9), which is likely key to CD1es rapid
lization with glucose monomycolate, showed lipid exchange rates. Additionally, the two
how the mycolate chain was bound in the con- pockets, again called A and F , are not clearly
tinuous superchannel made by the A , T , and separated from each other as in other CD1
F channels, which together have a maximum molecules and form a more open groove that
length of 70 A (112). Comparison with the other could also facilitate lipid exchange. Although
CD1 structures shows that CD1b is unique self lipids were found in the recombinant
in its capacity to bind long chain mycolate CD1e molecules used for crystallization, weak
lipids. electron density was observed in the structure,
The structure of CD1c in complex with potentially indicating that lipids can adopt
the mycobacterial antigen mannosyl-1- variable conformations in the antigen-binding
phosphomycoketide reveals a unique groove groove.
structure that contributes to CD1c having
the second-largest cavity of CD1 molecules
(Figure 9) (113). Two unique exit portals CD1-Specific T Cells
under the 1- and 2-helices, the D and E Because Group 1 CD1 molecules are not
portals, would allow longer chain lipids to exit expressed in mice, detailed studies of CD1a
into solvent. Most striking about CD1c is the c-restricted T cell development and function
open nature of the F pocket, which forms an lag behind those of CD1d-restricted NKT
open groove in lieu of a covered pocket. The cells. However, recent work has character-
nature of this groove would allow presentation ized the numbers, repertoire, and functional
of 12 amino acidlong lipopeptide antigens capacity of human Group 1 CD1restricted
that have been described as CD1c-restricted T T cells. CD1-reactive T cells comprise about
cell antigens (114). 10% of the human peripheral blood + T
Because the initial structure of murine cell repertoire, with CD1a-restricted cells
CD1d was determined in the absence of exoge- comprising a majority of both CD4+ and
nously added lipids, many subsequent struc- CD4/CD8 double-negative cell populations
tures have been determined with an array of self (118). The repertoire of CD1a-reactive cells
and bacteria-derived lipids. The structure of was broadly diverse in terms of TCR V and
human CD1d in complex with the potent NKT V gene segment usage and in terms of partic-
cell agonist GalCer shows the C26 fatty acyl ular cytokine secretion. Correlating with the
occupying the A pocket via a distinct curvature high CD1a expression level by skin-resident
around a central pole and the phytosphingosine Langerhans cells, the pool of CD1a-reactive
chain within the F pocket (Figure 9). CD1d T cells expressed skin-homing markers and
can also present lysophospholipids; a recent expressed IL-22, a cytokine thought to have
crystal structure of CD1d bound to lysophos- roles in skin immunity and homeostasis (119).

The development of CD1b-tetramers showed of the interaction footprint, with the germ-
that GMM-specic T cells from tuberculosis- line-encoded residues providing key contacts
infected patients, but not healthy controls, can to both CD1d and the GalCer head group.
be detected and are predominantly CD4+ Residues contributed by the J18 segment in
T cells (120). Both (121) and T cells the CDR3 contribute the most energetically
can respond to CD1c; those of the lineage important contacts (129, reviewed in 130). In-
respond to CD1c-presented sulfatide by terestingly, in subsequent structures with struc-
producing Th1 or Th2 cytokines (122) and can turally distinct self and bacterial lipids, mouse
exert cytotoxicity against CD1c-transfected iNKT TCRs still dock in a nearly identi-
C1R target cells (118). cal conformation; the TCR instead forces the
Given that CD1d is expressed in mice as lipid head group to adopt a position optimal
well as humans, investigators have been able to for binding (131, 132), although structures of
extensively characterize CD1d-restricted NKT human CD1d/NKT TCRs exhibit a greater
cells. Two NKT subsets have been described. docking variation on the CD1 surface (Fig-
Type I, or invariant, NKT cells (iNKT) ex- ure 10a) (115, 128, 131). The structures of
press an invariant V (V14 in mice, V24 type II NKT TCRs in complex with sulfatide-
in humans rearranged to their respective J18 and lysosulfatide-loaded CD1d have been de-
segments) chain, express a highly restricted termined recently and differ strikingly from
V chain, and potently respond to GalCer, the type I NKT TCR complexes (Figure 10b)
whereas type II NKT cells use diverse V gene (133, 134). The TCRs are docked in a nearly
segments and are not stimulated by GalCer. perpendicular fashion to the CD1d -helical
Much is known about type I NKT cell biology axis, a mode more similar to that of MHCp
owing to the identication of the GalCer ag- recognition by TCRs. The - and -chains
onist. In mice, they comprise 0.5% of periph- contribute equally to the CD1d docking foot-
eral blood T cells and up to 30% of T cells in the print, and there are important contacts pro-
liver, whereas in humans they are less frequent vided by non-germ-line-encoded residues of
but their percentages highly variable. NKT the CDR3 and CDR3 loops, again making
cells are implicated in various disease states, in- their global docking strategy more similar to
cluding autoimmunity, allergy, and bacterial in- conventional MHCp/ TCRs than to iNKT
fections (89). In some cases, rather than directly TCRs. However, like the iNKT TCRs, the sul-
responding to bacteria-derived lipids, they can fatide head group was contacted solely with a
be activated by upregulation of agonist self single chain () but did not form an intricate
lipids (123, 124). Type II NKT cells can re- hydrogen-bonding network as occurs in iNKT
spond to the self lipid sulfatide (125) and can TCR-GalCer recognition.
suppress autoimmunity and antitumor immu-
nity (126, 127).
EPCR: A CD1-Like Molecule

Endothelial cell protein C receptor (EPCR)
Molecular Basis of TCR Recognition shares 20% sequence homology with CD1 fam-
of CD1d ily members yet is not encoded within the CD1
To date, ternary TCR-lipid-CD1 complexes or the MHC locus. It contains a transmembrane
have been determined only for CD1d. The domain like the CD1 family members yet lacks
rst structure showed a human iNKT TCR the 3 domain and therefore does not associate
in complex with CD1d-GalCer (128), reveal- with 2 m. EPCRs most well-known function
ing a completely different TCR docking mode is as an anticoagulant, by directly binding to and
than that for MHCp molecules (Figure 10a) activating protein C to promote an anticlotting
(128). The invariant -chain contributes 66% pathway. The crystal structure of human EPCR
548 Adams Luoma

a TCR/GalCer b TCR/sulfatide
TCR/GalCer TCR/LPC TCR/lysosulfatide
1 1
3 2 2 1
1
3
2
3
2
1 2
1
3
CD1d
CD1d 2
Figure 10
NKT TCR recognition. (a) Comparison of the type I, iNKT TCR CDR loops from three different human
CD1d-lipid ternary structures. Shown are the CDR loops of iNKT TCRs in complex with human CD1d
(white surface) presenting -galactosylceramide (GalCer, pink) (3HUJ), lysophosphatidylcholine (LPC) in
pale blue (3TZV), and -galactosylceramide (GalCer) in yellow (3SDX). Despite the different nature of
the lipid ligands, the TCRs dock in a similar way, particularly the contacts of the CDR3 loop. The lipids
are instead forced to adopt a conformation permissive for TCR docking. The TCR adopts a parallel docking
orientation, shown by a red line. (b) Comparison of type II NKT TCR recognition of sulfatide (PDB ID:
4EI5) and lysosulfatide (PDB ID: 4ELM), shown in yellow and blue, respectively. The TCRs contact CD1d
lipid using all six CDR loops, in contrast to the iNKT TCRs. The docking orientation is completely
different from that of the iNKT TCRs, with a nearly perpendicular orientation of the TCRs relative to the
CD1d -helical axis, shown by a red line.
revealed a hydrophobic binding groove capable CD1d-LPC

of binding to phospholipids (135), which was EPCR-PE
later identied as phosphatidylcholine (136).
EPCR is also capable of binding the single-
chain lipid LPC with even higher afnity, which
interestingly impaired its binding to protein C 1
(136). A comparison of the crystal structures of
EPCR with that of human CD1d (1 and 2
domains) bound to LPC shows a striking over-
lap (RMSD 1.3 A), with the fatty acid chain 2
of LPC in CD1d and endogenous fatty acid
12.5
in EPCR accommodated similarly (Figure 11)
(115). However, the head groups were shifted
Figure 11
laterally by 12.5 A. A role for EPCR as a lym-
Comparison of the platform domains of endothelial
phocyte ligand had not been shown until very cell protein C receptor (EPCR) and CD1d. Shown
recently (137). These studies found that EPCR from the top are the structures of human EPCR
can directly bind human T cells of the lin- with modeled phosphatidylethanolamine (PE) in
eage and trigger activation through a multi- light purple (1L8J) and human CD1d with
molecular stress-induced complex. Unlike all lysophosphatidylcholine (LPC) in light yellow
(3U0P). The backbone RMSD of the alignment is
studies of CD1 recognition by T cells, the lipid 1.3 A, and the fatty acids within the A pocket
ligand-binding face of EPCR did not appear closely superimpose. The head-group position is
to have a role, suggesting a completely novel shifted signicantly, with the phosphate moieties
mechanism of TCR engagement. 12.5 A apart.

THE NKG2D LIGANDS: mology to ULBP1 and 2, additional members

ULBPs/RAE-1, H60, AND of the ULBP family were characterized; these
MICA/MICB are called ULBP3, ULBP4, RaeT1g/ULBP5,
and RaeT1L/ULBP6 (reviewed in 140). Five
The NKG2D Ligand Family Members closely related Rae-1 (retinoic acid early tran-
Share the MHC Fold script 1) family members have been character-
The proteins that are most divergent from the ized in the mouse (Rae-1, Rae-1, Rae-1,
classical class I molecules are members of a phy- Rae-1, and Rae-1) as well as three H60 (his-
logenetically related family that serve as stim- tocompatibility 60) members: H60a, H60b, and
H60c (Figure 2). Mice also express a more
ulatory ligands for the NKG2D receptor (138)

in mice and humans. This family is composed distantly related ULBP/Rae-1 family member,
of the ULBP/Rae-1 and H60 molecules. The MULT1 (murine UL16-binding protein-like
ULBP designation derives from the initial char- transcript 1). Overall the ULBP/Rae-1/H60
acterization of human ULBP1 and 2, which family members share low amino acid iden-
were discovered through their association with tity with the classical class I molecules (23%
the human CMV protein UL16; thus the term between the 1/2 domains); MULT1 shares
ULBP comes from UL16-binding proteins approximately 20%, whereas the MIC pro-
(139). Members of the family are phyloge- teins have closer identity of approximately 35%
netically distinct from the human MICA and within these domains.
MICB, yet all engage NKG2D in a similar fash- Along with their sequence divergence,
ion. As we discuss below, UL16 is an immune- NKG2D ligands also vary in their domain
evasion protein encoded by CMV that inhibits architecture. Expression for all is independent
the cell surface expression of MICB, ULBP1, of 2 m; MICA and MICB have the classical
ULBP2, and ULBP6. Based on sequence ho- 1/2/3 domain architecture, whereas the
remaining ligands have discarded the 3
domain and exist as just the 1/2 platform
(Figure 12a, left column). ULBP13, ULBP6,
NKG2D Rae-1, and H60c are attached to the cell
surface membrane via glycosylphosphatidyl-
NKG2D is an activating receptor expressed on T cells and NK inositol anchors, whereas MICA, MICB,
cells (reviewed in 138, 140). Structurally, it is a member of the ULBP4, ULBP5, H60a, and H60b have
C-type lectin family, similar to other NK receptors such as Ly49 transmembrane domains with cytoplasmic tails
(in the mouse) and CD94 and the other NKG2 family members. of varying length. The crystal structures of
NKG2D cannot signal on its own; instead, it associates with ULBP3 (141), Rae-1 (142), MICA (143, 144),
signaling adaptors via charged residues in its transmembrane and MICB (145) reveal platform domains that
domain. This signaling adaptor is called DAP10; in the mouse, have partially closed (MICA/MICB) or com-
NKG2D can have two alternatively spliced forms, one with a long pletely closed (Rae-1 and ULBP3) grooves
and the other with a short intracellular tail. The short form of (Figure 12a, middle and right columns; Figure
NKG2D can associate only with DAP10, and the long form can 12b), supporting previous evidence that these
pair either with DAP10 or with another related adaptor protein, molecules do not present peptides or other
DAP12. NKG2D, along with other activating receptors on NK small ligands. Differences in the positions of the
cells, is an important stimulatory signal that can be balanced by 1- and 2-helices between the MIC structures
counterinhibitory signaling to balance NK cell killing in the pe- and those of ULBP3 and Rae-1 (Figure 12b)
riphery. When inhibitory signals are absent (such as when MHC are consistent with their phylogenetic distance,
class I molecules are absent on the target cell), the activating with an average RMSD of 3.1 A between these
receptors dominate, and the NK cell is activated to kill. NKG2D structures. Along these lines, these ligands, in
can also perform costimulatory roles on and T cells. particular MICA and MICB, also exhibit a high
degree of polymorphism. Currently, 71 and 26
550 Adams Luoma

NKG2D
a 1
c
ULBP3 1 A B
2
2
MICA
1
Rae-1 1
1
2 UL16 2
2
1
MICB
MICA
2
1
1
2
2
3
96
1
MICB b D65
2 1
D163 A159
A162
T155
3 2 R158
UL16
HLA-A2 MICB
Figure 12
Divergent MHC structures and degenerate recognition of NKG2D ligands. (a) Ribbon diagrams from the side (left column) and top
(middle column) of the NKG2D ligands ULBP3 (red, PDB ID: 1KCG), Rae-1 ( purple, PDB ID: 1JFM), MICA ( yellow and orange, PDB
IDs: 1HYR and 1B3J, respectively), and MICB (blue, PDB ID: 1JE6). Both the liganded ( yellow) and unliganded (orange) structures of
MICA are shown, with the 96 angle shown for the conformations of the two 3 domains. Shown in the right column are surface
representations of ULBP3, Rae-1, and MICA, with their corresponding footprints of NKG2D mapped onto their surfaces [PDB IDs:
1KCG for ULBP2/NKG2D and 1HYR for MICA/NKG2D; Rae-1 was modeled from the low-resolution complex, 1JSK with 1JFM
(Rae-1), and 1HQ8 (NKG2D)]. The footprint of monomer A of NKG2D is colored pale cyan, monomer B, green. The footprints of
the recognition triadNKG2D residues Y152, M184, and Y199 in human, and Y168, I200, and Y215 in mousefor each monomer
are outlined in light pink. (b) Superposition of the structures of the NKG2D ligands shown in thin tubes onto that of HLA-A2 (PDB
ID: 1DUZ). (c) Ribbon diagram of the complex structure of MICA ( yellow) with NKG2D (cyan and green) (top, PDB ID: 1HYR) to
compare with that of UL16 (light purple) with MICB (blue) (middle, PDB ID: 2WY3). Bottom: surface representation of MICB with the
footprint of UL16 shown in light purple. Residues used by both NKG2D and UL16 are colored dark purple and labeled.
alleles that differ in the amino acid sequence are tail, eliminating the sorting sequence used for
segregating for MICA and MICB, respectively MICA trafcking. This allele is resistant to
(http://www.ebi.ac.uk/imgt/hla/align.html). intracellular retention by the CMV protein
One of the more interesting allelic forms of UL142 (146), which targets full-length MICA
MICA (MICA 008) found at high frequency via this motif. Interestingly, structural pre-
in several ethnic groups has a polymorphism diction suggests that UL142 also adopts the
that results in truncation of its cytoplasmic characteristic MHC fold (147) and is thus one

of many viral MHC homologs used in immune and binding, straddling the 1 and 2 domains
evasion (discussed at the end of this review). of each ligand with an overlapping footprint on
The variation in the sequences, structures, each surface (Figure 12a,c). A rigid adaptation
and expression regulation (reviewed in 140) model was proposed to explain this highly de-
of these MHC-like NKG2D ligands could be generate recognition (149), as NKG2D does
evolutionary efforts to counter viral immune- not undergo any gross conformational changes
evasion mechanisms (discussed below), yet or induced t to conform to each unique sur-
despite their divergence they still maintain face. Instead, a recognition triad composed of
effective associations with the monomorphic a set of three amino acids on each monomer
NKG2D receptor. was noted that makes key interactions with each
ligand surface. Y152, M184, and Y199 in hu-

man and Y168, I200, and Y215 in mouse con-
Degenerate Recognition by NKG2D tact residues of similar position between MICA,
The NKG2D ligands and their allelic variants ULBP3, and Rae-1, forming the core recog-
(148) are recognized by NKG2D with a range nition determinants of NKG2Ds binding. In
of afnities (Table 1), and their dissociation some cases, the contacted residues are con-
constants vary from the low M to low M served between the three ligands; for example,
(Table 1). Despite the low sequence homol- Y152 (Y168 in mouse) of monomer A contacts
ogy between the ligands, they are recognized R74 (MICA), R82 (ULBP3), and R73 (Rae-1),
by NKG2D in a remarkably conserved fashion. and Y199 (Y215 in mouse) of monomer B con-
Crystal structures of NKG2D in complex with tacts D163 (MICA), D169 (ULBP3), and E159
MICA (144), ULBP3 (141), and Rae-1 (142) (Rae-1) (150). In many cases, the residues con-
reveal how this receptor binds to each ligand. tacted are of a different chemical or structural
Both monomers of NKG2D participate in lig- nature; the residues in this triad have adapted to
these different contact environments, in some
cases making hydrophobic contacts with one
Table 1 Binding affinities of NKG2D ligands
ligand while forming hydrogen bonds with an-
to NKG2D and UL16, an immune-evasion
other (150). The footprints of the recognition
protein
triads from both monomers on the three ligands
Ligand Receptor Affinity (KD ) are shown in Figure 12a (right column, outlined
MICA NKG2D 60100 Ma in pink).
MICB NKG2D 800 Ma
MICB UL16 66 Mb
ULBP1 NKG2D 1.1 Ma
Viral Measures to Prevent NKG2D
Ligand Expression
ULBP1 UL16 12 Mb
Rae-1 NKG2D 690 Mc In general, NKG2D ligand expression is up-
Rae-1 NKG2D 345 Mc regulated on tumors and virally infected cells,
Rae-1 NKG2D 586 Mc providing a clear signal for NKG2D engage-
Rae-1 NKG2D 726 Mc ment for NK cells and in some cases CD8+
Rae-1 NKG2D 2080 Ma T cells and T cells (reviewed in 138,
H60a NKG2D 2030 Mc 140). Both human and mouse CMV (HCMV
H60b NKG2D 310 Mc
and MCMV, respectively) have evolved elabo-
rate mechanisms to prevent the expression of
H60c NKG2D 8.7 Mc
these MHC-like NKG2D ligands. HCMV en-
MULT1 NKG2D 6 Mc
codes the aforementioned UL146 and UL16
a
Adapted from Champsaur & Lanier (140). proteins that retain MICA (UL146), MICB,
b
Data reported by Muller et al. (145). ULBP1, ULBP2, and ULBP6 (UL16), within
c
Adapted from Samarakoon et al. (158). the cell, preventing cell surface expression.
552 Adams Luoma

MCMV has likewise evolved several proteins molecular basis behind MICAs ability to sub-
to retain murine NKG2D ligands intracellu- vert UL16 binding; Q169 in MICBs 2 do-
larly: m145, m152, and m155 target MULT1, main is an Arg in MICA, and this would lead
the Rae-1 family, and H60, respectively, and to a steric clash with UL16s M59 and L161.
m138 downregulates MULT1, Rae-1, and This position also segregates along the lines
H60 (reviewed in 138, 140). Using domain of UL16 reactivity, as the binders to UL16
swapping between MICB (which binds UL16) (MICB and ULBP1, 2, and 6) have either an Asp
and MICA (which does not bind UL16), the or a Gln, whereas the nonbinders (MICA and
putative recognition site of UL16 was mapped ULBP3 and 4) have an Arg. The highly diverse
to MICBs 2-helix (151). This was further re- repertoire of NKG2D ligands exists in part to
ned by the crystal structure of UL16 with subvert viral mechanisms of downregulation;
MICB (145), which provided detailed molec- their coevolution with a monomorphic recep-
ular insight into how this protein associates tor (NKG2D) requires a recognition code that
with its divergent ligands. Remarkably, UL16s can be conserved and translated across these
binding footprint on MICB overlaps the foot- many ligand family members. Viral hijacking
print mapped for NKG2D on MICA (144) as of at least part of this code is an effective way
well as the other NKG2D ligands and, be- to maintain recognition of many of these fam-
tween MICA and MICB, targets six particu- ily members and is an excellent example of the
lar residues (D65, T155, A159, A162, D163, host/pathogen arms race.
and R/H158) that are also bound by NKG2D
(Figure 12c, bottom). Several of these shared
residues are likely also important in UL16s de-
generate recognition of its ULBP ligands, given VIRAL MHC HOMOLOGS
that D163 is conserved in all NKG2D ligands, As discussed above, viruses have evolved in-
alanine and glycine are found at position 162, creasingly clever mechanisms for immune eva-
and position 159 can be variable in its chem- sion. Some of the best examples of this are ex-
istry and size yet is still used in the interface pression of MHC-like mimics by both HCMV
with NKG2D. This structure also provides the and MCMV. HCMV encodes two MHC-like
HLA-A2 UL18 m144 m153 m157

1 1 1
1 1
2
2 2 2
2
2m 2m 2m
1 1 1 1 1
2 2 2 2
Figure 13
Structures of virally encoded MHC homologs. The following are shown in comparison with HLA-A2 (white, PDB ID: 1DUZ): UL18
(light blue, PDB ID: 3D2U), m144 (light orange, PDB ID: 1U58), m153 (light green, PDB ID: 2O5N), and m157 ( pink, PDB ID 2NYK)
from the side (top) and from above (bottom).

proteins, UL18 and UL142, whereas MCMV have been identied in species that do not
encodes ve MHC-like proteins: m144, have adaptive immunity (in other words, the
m145, m152, m155, and m157. Two separate ability to generate recombined receptors like
strategies are employed by these molecules antibodies and T cells), raising questions re-
to modulate immune recognition: UL18 and garding the evolutionary development of this
m157 act as MHC mimics and are expressed on fold. Were MHC-like molecules originally
the cell surface, where they interact with acti- evolved to perform immune surveillance func-
vating or inhibitory NK cell receptors, whereas tions, such as what we see in the highly di-
m145, m152, m155, and UL142 downregulate vergent NKG2D ligands or lipid-presenting
the surface expression of MULT1, Rae-1, H60, CD1/EPCR molecules? Or was this fold spe-
and MICA, respectively (see 152 and references cialized for other nonimmune functions (such
therein). m144 contributes to a decrease in NK as that of ZAG or HFE) and then co-opted
cell lysis (153); however, the mechanism by by the adaptive or innate immune system for
which it performs this function remains unde- surveillance? Although there are no direct an-
ned. Crystal structures have been determined swers to these questions, insight into this area
for four of these CMV-encoded MHC-like is increasing as we better understand the role of
proteins: UL18 (154), m144 (155), m153 (156), MHC-like proteins in other species and how
and m157 (157) (Figure 13). UL18 and m144 this fold can be highly manipulated, for ex-
associate with 2 m for expression, whereas ample by viruses, to perform roles either re-
m153 and m157 are 2 m independent, having lated to their endogenous functions (like MHC
evolved a stabilizing network of interactions mimics for NK cell receptors) or counter to
between their 1/2 platforms and the 3 their functions, such as intracellular retention
domains. All of these proteins retain charac- of MHC-like ligands for the NKG2D recep-
teristics of the MHC fold, with an obvious tor. A theme that has been noted during study
platform structure of a -sheet topped by two of these MHC-like ligands is their recognition
-helices, yet each has modied this fold in par- by T cells via the TCR. With the exception of
ticular ways in order to perform their specic the NKG2D ligands, many of the remaining
functions in immune evasion (reviewed in 152). MHC-like molecules discussed in this review
are recognized by T cells. Whether all these
interactions are physiologically relevant is un-
CLOSING REMARKS clear. Could they just be a product of coevo-
The adaptability of the MHC fold is apparent lution of the TCR for the MHC surface? Or
in the molecules discussed in this review, both is the TCR/MHC interaction one that is func-
in the modications to its structure while pre- tionally maintained during the evolution of pro-
serving the core elements of the MHC fold and teins containing the MHC-like fold? These and
in the consequences of the altered structure on related questions await further studies, yet will
the proteins function (in immune surveillance provide insight into the evolution of this protein
or in nonimmune functions). Despite consid- structure and how it is used in host homeostasis
erable effort, few homologs of the MHC fold and protection.
DISCLOSURE STATEMENT
The authors are not aware of any afliations, memberships, funding, or nancial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
The authors were supported by NIH grant R01-AI073922.
554 Adams Luoma

LITERATURE CITED
1. Bjorkman PJ, Parham P. 1990. Structure, function, and diversity of class I major histocompatibility
complex molecules. Annu. Rev. Biochem. 59:25388
2. Rodgers JR, Cook RG. 2005. MHC class Ib molecules bridge innate and acquired immunity. Nat. Rev.
Immunol. 5:45971
3. Olson R, Dulac C, Bjorkman PJ. 2006. MHC homologs in the nervous systemthey havent lost their
groove. Curr. Opin. Neurobiol. 16:35157
4. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. 1987. Structure of the
human class I histocompatibility antigen, HLA-A2. Nature 329:50612
5. Hoare HL, Sullivan LC, Pietra G, Clements CS, Lee EJ, et al. 2006. Structural basis for a major
histocompatibility complex class Ib-restricted T cell response. Nat. Immunol. 7:25664

6. Kaiser BK, Pizarro JC, Kerns J, Strong RK. 2008. Structural basis for NKG2A/CD94 recognition of
HLA-E. Proc. Natl. Acad. Sci. USA 105:6696701
7. Petrie EJ, Clements CS, Lin J, Sullivan LC, Johnson D, et al. 2008. CD94-NKG2A recognition of
human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence. J. Exp. Med. 205:72535
8. Hoare HL, Sullivan LC, Clements CS, Ely LK, Beddoe T, et al. 2008. Subtle changes in peptide
conformation profoundly affect recognition of the non-classical MHC class I molecule HLA-E by the
CD94-NKG2 natural killer cell receptors. J. Mol. Biol. 377:1297303
9. OCallaghan CA, Tormo J, Willcox BE, Braud VM, Jakobsen BK, et al. 1998. Structural features impose
tight peptide binding specicity in the nonclassical MHC molecule HLA-E. Mol. Cell 1:53141
10. Strong RK, Holmes MA, Li P, Braun L, Lee N, Geraghty DE. 2003. HLA-E allelic variants. Corre-
lating differential expression, peptide afnities, crystal structures, and thermal stabilities. J. Biol. Chem.
278:508290
11. Shiroishi M, Kuroki K, Ose T, Rasubala L, Shiratori I, et al. 2006. Efcient leukocyte Ig-like receptor
signaling and crystal structure of disulde-linked HLA-G dimer. J. Biol. Chem. 281:1043947
12. Clements CS, Kjer-Nielsen L, Kostenko L, Hoare HL, Dunstone MA, et al. 2005. Crystal structure of
HLA-G: a nonclassical MHC class I molecule expressed at the fetal-maternal interface. Proc. Natl. Acad.
Sci. USA 102:336065
13. Shiroishi M, Kuroki K, Rasubala L, Tsumoto K, Kumagai I, et al. 2006. Structural basis for
recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2
(LILRB2/LIR2/ILT4/CD85d). Proc. Natl. Acad. Sci. USA 103:1641217
14. Walpole NG, Kjer-Nielsen L, Kostenko L, McCluskey J, Brooks AG, et al. 2010. The structure and
stability of the monomorphic HLA-G are inuenced by the nature of the bound peptide. J. Mol. Biol.
397:46780
15. Wang CR, Castano AR, Peterson PA, Slaughter C, Lindahl KF, Deisenhofer J. 1995. Nonclassical
binding of formylated peptide in crystal structure of the MHC class Ib molecule H2-M3. Cell 82:65564
16. Zeng L, Sullivan LC, Vivian JP, Walpole NG, Harpur CM, et al. 2012. A structural basis for antigen
presentation by the MHC class Ib molecule, Qa-1b. J. Immunol. 188:30210
17. He X, Tabaczewski P, Ho J, Stroynowski I, Garcia KC. 2001. Promiscuous antigen presentation by
the nonclassical MHC Ib Qa-2 is enabled by a shallow, hydrophobic groove and self-stabilized peptide
conformation. Structure 9:121324
18. Joly E, Rouillon V. 2006. The orthology of HLA-E and H2-Qa1 is hidden by their concerted evolution
with other MHC class I molecules. Biol. Direct. 1:2
19. Comiskey M, Goldstein CY, De Fazio SR, Mammolenti M, Newmark JA, Warner CM. 2003. Evidence
that HLA-G is the functional homolog of mouse Qa-2, the Ped gene product. Hum. Immunol. 64:999
1004
20. Braud V, Jones EY, McMichael A. 1997. The human major histocompatibility complex class Ib molecule
HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9. Eur.
J. Immunol. 27:116469
21. Aldrich CJ, DeCloux A, Woods AS, Cotter RJ, Soloski MJ, Forman J. 1994. Identication of a Tap-
dependent leader peptide recognized by alloreactive T cells specic for a class Ib antigen. Cell 79:64958

22. Braud VM, Allan DS, OCallaghan CA, Soderstrom K, DAndrea A, et al. 1998. HLA-E binds to natural
killer cell receptors CD94/NKG2A, B and C. Nature 391:79599
23. Vance RE, Kraft JR, Altman JD, Jensen PE, Raulet DH. 1998. Mouse CD94/NKG2A is a natural killer
cell receptor for the nonclassical major histocompatibility complex (MHC) class I molecule Qa-1(b). J.
Exp. Med. 188:184148
24. Pietra G, Romagnani C, Moretta L, Mingari MC. 2009. HLA-E and HLA-E-bound peptides: recogni-
tion by subsets of NK and T cells. Curr. Pharm. Des. 15:333644
25. Sullivan LC, Hoare HL, McCluskey J, Rossjohn J, Brooks AG. 2006. A structural perspective on MHC
class Ib molecules in adaptive immunity. Trends Immunol. 27:41320
26. Allan DS, Colonna M, Lanier LL, Churakova TD, Abrams JS, et al. 1999. Tetrameric complexes of
human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells.
J. Exp. Med. 189:114956
27. Ponte M, Cantoni C, Biassoni R, Tradori-Cappai A, Bentivoglio G, et al. 1999. Inhibitory receptors
sensing HLA-G1 molecules in pregnancy: decidua-associated natural killer cells express LIR-1 and
CD94/NKG2A and acquire p49, an HLA-G1-specic receptor. Proc. Natl. Acad. Sci. USA 96:567479
28. Rajagopalan S, Long EO. 1999. A human histocompatibility leukocyte antigen (HLA)-G-specic recep-
tor expressed on all natural killer cells. J. Exp. Med. 189:1093100
29. Gomes AQ, Correia DV, Silva-Santos B. 2007. Non-classical major histocompatibility complex proteins
as determinants of tumour immunosurveillance. EMBO Rep. 8:102430
30. Lee N, Malacko AR, Ishitani A, Chen MC, Bajorath J, et al. 1995. The membrane-bound and soluble
forms of HLA-G bind identical sets of endogenous peptides but differ with respect to TAP association.
Immunity 3:591600
31. Joyce S, Tabaczewski P, Angeletti RH, Nathenson SG, Stroynowski I. 1994. A nonpolymorphic major
histocompatibility complex class Ib molecule binds a large array of diverse self-peptides. J. Exp. Med.
179:57988
32. Rotzschke O, Falk K, Stevanovic S, Grahovac B, Soloski MJ, et al. 1993. Qa-2 molecules are peptide
receptors of higher stringency than ordinary class I molecules. Nature 361:64244
33. Tabaczewski P, Chiang E, Henson M, Stroynowski I. 1997. Alternative peptide binding motifs of Qa-2
class Ib molecules dene rules for binding of self and nonself peptides. J. Immunol. 159:277181
34. Ishitani A, Sageshima N, Lee N, Dorofeeva N, Hatake K, et al. 2003. Protein expression and peptide
binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental
immune recognition. J. Immunol. 171:137684
35. Munz C, Stevanovic S, Rammensee HG. 1999. Peptide presentation and NK inhibition by HLA-G.
J. Reprod. Immunol. 43:13955
36. Willcox BE, Thomas LM, Bjorkman PJ. 2003. Crystal structure of HLA-A2 bound to LIR-1, a host and
viral major histocompatibility complex receptor. Nat. Immunol. 4:91319
37. Boyson JE, Erskine R, Whitman MC, Chiu M, Lau JM, et al. 2002. Disulde bond-mediated dimerization
of HLA-G on the cell surface. Proc. Natl. Acad. Sci. USA 99:1618085
38. Gonen-Gross T, Achdout H, Gazit R, Hanna J, Mizrahi S, et al. 2003. Complexes of HLA-G protein
on the cell surface are important for leukocyte Ig-like receptor-1 function. J. Immunol. 171:134351
39. Yan WH, Fan LA. 2005. Residues Met76 and Gln79 in HLA-G1 domain involved in KIR2DL4 recog-
nition. Cell Res. 15:17682
40. Shawar SM, Cook RG, Rodgers JR, Rich RR. 1990. Specialized functions of MHC class I molecules.
I. An N-formyl peptide receptor is required for construction of the class I antigen Mta. J. Exp. Med.
171:897912
41. Smith GP, Dabhi VM, Pamer EG, Lindahl KF. 1994. Peptide presentation by the MHC class Ib
molecule, H2-M3. Int. Immunol. 6:191726
42. Vyas JM, Rodgers JR, Rich RR. 1995. H-2M3a violates the paradigm for major histocompatibility
complex class I peptide binding. J. Exp. Med. 181:181725
43. Lenz LL, Bevan MJ. 1997. CTL responses to H2-M3-restricted Listeria epitopes. Immunol. Rev. 158:115
21
556 Adams Luoma

44. Gulden PH, Fischer P 3rd, Sherman NE, Wang W, Engelhard VH, et al. 1996. A Listeria monocytogenes
pentapeptide is presented to cytolytic T lymphocytes by the H2-M3 MHC class Ib molecule. Immunity
5:7379
45. Leishman AJ, Naidenko OV, Attinger A, Koning F, Lena CJ, et al. 2001. T cell responses modulated
through interaction between CD8 and the nonclassical MHC class I molecule, TL. Science 294:1936
39
46. Huang Y, Park Y, Wang-Zhu Y, Larange A, Arens R, et al. 2011. Mucosal memory CD8+ T cells are
selected in the periphery by an MHC class I molecule. Nat. Immunol. 12:108695
47. Chien YH, Konigshofer Y. 2007. Antigen recognition by T cells. Immunol. Rev. 215:4658
48. Hershberg R, Eghtesady P, Sydora B, Brorson K, Cheroutre H, et al. 1990. Expression of the thymus
leukemia antigen in mouse intestinal epithelium. Proc. Natl. Acad. Sci. USA 87:972731
49. Wu M, van Kaer L, Itohara S, Tonegawa S. 1991. Highly restricted expression of the thymus leukemia
antigens on intestinal epithelial cells. J. Exp. Med. 174:21318
50. Madakamutil LT, Christen U, Lena CJ, Wang-Zhu Y, Attinger A, et al. 2004. CD8-mediated survival
and differentiation of CD8 memory T cell precursors. Science 304:59093

51. Liu Y, Xiong Y, Naidenko OV, Liu JH, Zhang R, et al. 2003. The crystal structure of a TL/CD8
complex at 2.1 A resolution: implications for modulation of T cell activation and memory. Immunity
18:20515
52. Adams EJ, Chien YH, Garcia KC. 2005. Structure of a T cell receptor in complex with the nonclassical
MHC T22. Science 308:22731
53. Adams EJ, Strop P, Shin S, Chien YH, Garcia KC. 2008. An autonomous CDR3 is sufcient for
recognition of the nonclassical MHC class I molecules T10 and T22 by T cells. Nat. Immunol.
9:77784
54. Boulanger LM. 2004. MHC class I in activity-dependent structural and functional plasticity. Neuron Glia
Biol. 1:28389
55. Wingren C, Crowley MP, Degano M, Chien Y, Wilson IA. 2000. Crystal structure of a T cell receptor
ligand T22: a truncated MHC-like fold. Science 287:31014
56. Jensen KD, Su X, Shin S, Li L, Youssef S, et al. 2008. Thymic selection determines T cell effector
fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon . Immunity
29:90100
57. Shin S, El-Diwany R, Schaffert S, Adams EJ, Garcia KC, et al. 2005. Antigen recognition determinants
of T cell receptors. Science 308:25255
58. Sandstrom A, Scharf L, McRae G, Hawk AJ, Meredith SC, Adams EJ. 2012. T cell receptors recognize
the non-classical major histocompatibility complex (MHC) molecule T22 via conserved anchor residues
in a MHC peptide-like fashion. J. Biol. Chem. 287:603543
59. Olson R, Huey-Tubman KE, Dulac C, Bjorkman PJ. 2005. Structure of a pheromone receptor-associated
MHC molecule with an open and empty groove. PLoS Biol. 3:e257
60. Tada T, Ohkubo I, Niwa M, Sasaki M, Tateyama H, Eimoto T. 1991. Immunohistochemical localization
of Zn- 2-glycoprotein in normal human tissues. J. Histochem. Cytochem. 39:122126
61. Hirai K, Hussey HJ, Barber MD, Price SA, Tisdale MJ. 1998. Biological evaluation of a lipid-mobilizing
factor isolated from the urine of cancer patients. Cancer Res. 58:235965
62. Todorov PT, McDevitt TM, Meyer DJ, Ueyama H, Ohkubo I, Tisdale MJ. 1998. Purication and
characterization of a tumor lipid-mobilizing factor. Cancer Res. 58:235358
63. Sanchez LM, Chirino AJ, Bjorkman P. 1999. Crystal structure of human ZAG, a fat-depleting factor
related to MHC molecules. Science 283:191419
64. Delker SL, West AP Jr, McDermott L, Kennedy MW, Bjorkman PJ. 2004. Crystallographic studies of
ligand binding by Zn-2-glycoprotein. J. Struct. Biol. 148:20513
65. McDermott LC, Freel JA, West AP, Bjorkman PJ, Kennedy MW. 2006. Zn-2-glycoprotein, an MHC
class I-related glycoprotein regulator of adipose tissues: modication or abrogation of ligand binding by
site-directed mutagenesis. Biochemistry 45:203541
66. Russell ST, Tisdale MJ. 2012. Role of -adrenergic receptors in the anti-obesity and anti-diabetic effects
of zinc-2-glycoprotien (ZAG). Biochim. Biophys. Acta 1821:59099

67. Rolli V, Radosavljevic M, Astier V, Macquin C, Castan-Laurell I, et al. 2007. Lipolysis is altered in MHC
class I zinc-(2)-glycoprotein decient mice. FEBS Lett. 581:394400
68. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, et al. 1996. A novel MHC class Ilike gene
is mutated in patients with hereditary haemochromatosis. Nat. Genet. 13:399408
69. Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. 1997. Global prevalence of putative
haemochromatosis mutations. J. Med. Genet. 34:27578
70. Feder JN, Penny DM, Irrinki A, Lee VK, Lebron JA, et al. 1998. The hemochromatosis gene product
complexes with the transferrin receptor and lowers its afnity for ligand binding. Proc. Natl. Acad. Sci.
USA 95:147277
71. Parkkila S, Waheed A, Britton RS, Bacon BR, Zhou XY, et al. 1997. Association of the transferrin
receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc. Natl.
Acad. Sci. USA 94:13198202
72. Lebron JA, Bennett MJ, Vaughn DE, Chirino AJ, Snow PM, et al. 1998. Crystal structure of the
hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell
93:11123
73. Bennett MJ, Lebron JA, Bjorkman PJ. 2000. Crystal structure of the hereditary haemochromatosis
protein HFE complexed with transferrin receptor. Nature 403:4653
74. Ganz T. 2008. Iron homeostasis: tting the puzzle pieces together. Cell Metab. 7:28890
75. Rohrlich PS, Fazilleau N, Ginhoux F, Firat H, Michel F, et al. 2005. Direct recognition by cytolytic
T cells of Hfe, a MHC class Ib molecule without antigen-presenting function. Proc. Natl. Acad. Sci. USA
102:1285560
76. Boucherma R, Kridane-Miledi H, Vives FL, Vauchy C, Borg C, et al. 2012. Loss of central and peripheral
CD8+ T-cell tolerance to HFE in mouse models of human familial hemochromatosis. Eur. J. Immunol.
42:85162
77. Simister NE, Mostov KE. 1989. An Fc receptor structurally related to MHC class I antigens. Nature
337:18487
78. Simister NE, Rees AR. 1985. Isolation and characterization of an Fc receptor from neonatal rat small
intestine. Eur. J. Immunol. 15:73338
79. Baker K, Qiao SW, Kuo T, Kobayashi K, Yoshida M, et al. 2009. Immune and non-immune functions
of the (not so) neonatal Fc receptor, FcRn. Semin. Immunopathol. 31:22336
80. Kuo TT, Baker K, Yoshida M, Qiao SW, Aveson VG, et al. 2010. Neonatal Fc receptor: from immunity
to therapeutics. J. Clin. Immunol. 30:77789
81. Qiao SW, Kobayashi K, Johansen FE, Sollid LM, Andersen JT, et al. 2008. Dependence of antibody-
mediated presentation of antigen on FcRn. Proc. Natl. Acad. Sci. USA 105:933742
82. Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, et al. 2003. The major histocompatibility
complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J. Exp. Med.
197:31522
83. Kobayashi K, Qiao SW, Yoshida M, Baker K, Lencer WI, Blumberg RS. 2009. An FcRn-dependent role
for anti-agellin immunoglobulin G in pathogenesis of colitis in mice. Gastroenterology 137:174656.e1
84. Burmeister WP, Gastinel LN, Simister NE, Blum ML, Bjorkman PJ. 1994. Crystal structure at 2.2 A
resolution of the MHC-related neonatal Fc receptor. Nature 372:33643
85. Burmeister WP, Huber AH, Bjorkman PJ. 1994. Crystal structure of the complex of rat neonatal Fc
receptor with Fc. Nature 372:37983
86. Martin WL, West AP Jr, Gan L, Bjorkman PJ. 2001. Crystal structure at 2.8 A of an FcRn/heterodimeric
Fc complex: mechanism of pH-dependent binding. Mol. Cell 7:86777
87. Kasahara M, Yoshida S. 2012. Immunogenetics of the NKG2D ligand gene family. Immunogenetics
64:85567
88. Rabinovich BA, Ketchem RR, Wolfson M, Goldstein L, Skelly M, Cosman D. 2008. A role for the MHC
class Ilike Mill molecules in nutrient metabolism and wound healing. Immunol. Cell Biol. 86:48996
89. Bendelac A, Savage PB, Teyton L. 2007. The biology of NKT cells. Annu. Rev. Immunol. 25:297336
90. Brigl M, Brenner MB. 2004. CD1: antigen presentation and T cell function. Annu. Rev. Immunol.
22:81790
558 Adams Luoma

91. Dascher CC. 2007. Evolutionary biology of CD1. Curr. Top. Microbiol. Immunol. 314:326
92. Porcelli S, Morita CT, Brenner MB. 1992. CD1b restricts the response of human CD4-8- T lymphocytes
to a microbial antigen. Nature 360:59397
93. Porcelli S, Brenner MB, Greenstein JL, Balk SP, Terhorst C, Bleicher PA. 1989. Recognition of cluster
of differentiation 1 antigens by human CD4 CD8 cytolytic T lymphocytes. Nature 341:44750
94. Beckman EM, Porcelli SA, Morita CT, Behar SM, Furlong ST, Brenner MB. 1994. Recognition of a
lipid antigen by CD1-restricted + T cells. Nature 372:69194
95. Zeng Z, Castano AR, Segelke BW, Stura EA, Peterson PA, Wilson IA. 1997. Crystal structure of mouse
CD1: an MHC-like fold with a large hydrophobic binding groove. Science 277:33945
96. Bendelac A, Lantz O, Quimby ME, Yewdell JW, Bennink JR, Brutkiewicz RR. 1995. CD1 recognition
by mouse NK1+ T lymphocytes. Science 268:86365
97. Dougan SK, Kaser A, Blumberg RS. 2007. CD1 expression on antigen-presenting cells. Curr. Top.
Microbiol. Immunol. 314:11341
98. Barral DC, Brenner MB. 2007. CD1 antigen presentation: how it works. Nat. Rev. Immunol. 7:92941
99. Salio M, Silk JD, Cerundolo V. 2010. Recent advances in processing and presentation of CD1 bound
lipid antigens. Curr. Opin. Immunol. 22:8188
100. De Libero G, Mori L. 2012. Novel insights into lipid antigen presentation. Trends Immunol. 33:10311
101. Mori L, De Libero G. 2012. T cells specic for lipid antigens. Immunol. Res. 53:19199
102. Moody DB, Young DC, Cheng TY, Rosat JP, Roura-Mir C, et al. 2004. T cell activation by lipopeptide
antigens. Science 303:52731
103. Moody DB, Ulrichs T, Muhlecker W, Young DC, Gurcha SS, et al. 2000. CD1c-mediated T-cell
recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature 404:88488
104. Kobayashi E, Motoki K, Uchida T, Fukushima H, Koezuka Y. 1995. KRN7000, a novel immunomod-
ulator, and its antitumor activities. Oncol. Res. 7:52934
105. Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, et al. 1997. CD1d-restricted and TCR-mediated
activation of V14 NKT cells by glycosylceramides. Science 278:162629
106. Kinjo Y, Wu D, Kim G, Xing GW, Poles MA, et al. 2005. Recognition of bacterial glycosphingolipids
by natural killer T cells. Nature 434:52025
107. Mattner J, Debord KL, Ismail N, Goff RD, Cantu C 3rd, et al. 2005. Exogenous and endogenous
glycolipid antigens activate NKT cells during microbial infections. Nature 434:52529
108. Kinjo Y, Tupin E, Wu D, Fujio M, Garcia-Navarro R, et al. 2006. Natural killer T cells recognize
diacylglycerol antigens from pathogenic bacteria. Nat. Immunol. 7:97886
109. Zajonc DM, Elsliger MA, Teyton L, Wilson IA. 2003. Crystal structure of CD1a in complex with a
sulfatide self antigen at a resolution of 2.15 A. Nat. Immunol. 4:80815
110. Zajonc DM, Crispin MD, Bowden TA, Young DC, Cheng TY, et al. 2005. Molecular mechanism of
lipopeptide presentation by CD1a. Immunity 22:20919
111. Gadola SD, Zaccai NR, Harlos K, Shepherd D, Castro-Palomino JC, et al. 2002. Structure of human
CD1b with bound ligands at 2.3 A, a maze for alkyl chains. Nat. Immunol. 3:72126
112. Batuwangala T, Shepherd D, Gadola SD, Gibson KJ, Zaccai NR, et al. 2004. The crystal structure of
human CD1b with a bound bacterial glycolipid. J. Immunol. 172:238288
113. Scharf L, Li NS, Hawk AJ, Garzon D, Zhang T, et al. 2010. The 2.5 A structure of CD1c in complex with
a mycobacterial lipid reveals an open groove ideally suited for diverse antigen presentation. Immunity
33:85362
114. Van Rhijn I, Young DC, De Jong A, Vazquez J, Cheng TY, et al. 2009. CD1c bypasses lysosomes to
present a lipopeptide antigen with 12 amino acids. J. Exp. Med. 206:140922
115. Lopez-Sagaseta J, Sibener LV, Kung JE, Gumperz J, Adams EJ. 2012. Lysophospholipid presentation
by CD1d and recognition by a human natural killer T-cell receptor. EMBO J. 31:204759
116. Koch M, Stronge VS, Shepherd D, Gadola SD, Mathew B, et al. 2005. The crystal structure of human
CD1d with and without -galactosylceramide. Nat. Immunol. 6:81926
117. Garcia-Alles LF, Giacometti G, Versluis C, Maveyraud L, de Paepe D, et al. 2011. Crystal structure of
human CD1e reveals a groove suited for lipid-exchange processes. Proc. Natl. Acad. Sci. USA 108:13230
35

118. de Lalla C, Lepore M, Piccolo FM, Rinaldi A, Scelfo A, et al. 2011. High-frequency and adaptive-like
dynamics of human CD1 self-reactive T cells. Eur. J. Immunol. 41:60210
119. de Jong A, Pena-Cruz V, Cheng TY, Clark RA, Van Rhijn I, Moody DB. 2010. CD1a-autoreactive T
cells are a normal component of the human T cell repertoire. Nat. Immunol. 11:11029
120. Kasmar AG, van Rhijn I, Cheng TY, Turner M, Seshadri C, et al. 2011. CD1b tetramers bind T
cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans. J. Exp. Med.
208:174147
121. Spada FM, Grant EP, Peters PJ, Sugita M, Melian A, et al. 2000. Self-recognition of CD1 by / T
cells: implications for innate immunity. J. Exp. Med. 191:93748
122. Shamshiev A, Gober HJ, Donda A, Mazorra Z, Mori L, De Libero G. 2002. Presentation of the same
glycolipid by different CD1 molecules. J. Exp. Med. 195:101321

123. De Libero G, Moran AP, Gober HJ, Rossy E, Shamshiev A, et al. 2005. Bacterial infections promote T
cell recognition of self-glycolipids. Immunity 22:76372
124. Brennan PJ, Tatituri RV, Brigl M, Kim EY, Tuli A, et al. 2011. Invariant natural killer T cells recognize
lipid self antigen induced by microbial danger signals. Nat. Immunol. 12:120211
125. Jahng A, Maricic I, Aguilera C, Cardell S, Halder RC, Kumar V. 2004. Prevention of autoimmunity
by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. J. Exp. Med.
199:94757
126. Terabe M, Berzofsky JA. 2007. NKT cells in immunoregulation of tumor immunity: a new immunoreg-
ulatory axis. Trends Immunol. 28:49196
127. Subramanian L, Blumenfeld H, Tohn R, Ly D, Aguilera C, et al. 2012. NKT cells stimulated by long
fatty acyl chain sulfatides signicantly reduces the incidence of type 1 diabetes in nonobese diabetic mice.
PLoS ONE 7:e37771
128. Borg NA, Wun KS, Kjer-Nielsen L, Wilce MC, Pellicci DG, et al. 2007. CD1d-lipid-antigen recognition
by the semi-invariant NKT T-cell receptor. Nature 448:4449
129. Wun KS, Borg NA, Kjer-Nielsen L, Beddoe T, Koh R, et al. 2008. A minimal binding footprint on
CD1d-glycolipid is a basis for selection of the unique human NKT TCR. J. Exp. Med. 205:93949
130. Godfrey DI, Pellicci DG, Patel O, Kjer-Nielsen L, McCluskey J, Rossjohn J. 2010. Antigen recognition
by CD1d-restricted NKT T cell receptors. Semin. Immunol. 22:6167
131. Pellicci DG, Clarke AJ, Patel O, Mallevaey T, Beddoe T, et al. 2011. Recognition of -linked self
glycolipids mediated by natural killer T cell antigen receptors. Nat. Immunol. 12:82733
132. Li Y, Girardi E, Wang J, Yu ED, Painter GF, et al. 2010. The V14 invariant natural killer T cell TCR
forces microbial glycolipids and CD1d into a conserved binding mode. J. Exp. Med. 207:238393
133. Patel O, Pellicci DG, Gras S, Sandoval-Romero ML, Uldrich AP, et al. 2012. Recognition of CD1d-
sulfatide mediated by a type II natural killer T cell antigen receptor. Nat. Immunol. 13:85763
134. Girardi E, Maricic I, Wang J, Mac TT, Iyer P, et al. 2012. Type II natural killer T cells use features of
both innate-like and conventional T cells to recognize sulfatide self antigens. Nat. Immunol. 13:85156
135. Oganesyan V, Oganesyan N, Terzyan S, Qu D, Dauter Z, et al. 2002. The crystal structure of the
endothelial protein C receptor and a bound phospholipid. J. Biol. Chem. 277:2485154
136. Lopez-Sagaseta J, Puy C, Tamayo I, Allende M, Cervero J, et al. 2012. sPLA2-V inhibits EPCR anti-
coagulant and antiapoptotic properties by accommodating lysophosphatidylcholine or PAF in the hy-
drophobic groove. Blood 119:291421
137. Willcox CR, Pitard V, Netzer S, Couzi L, Salim M, et al. 2012. Cytomegalovirus and tumor stress
surveillance by binding of a human T cell antigen receptor to endothelial protein C receptor. Nat.
Immunol. 13:87279
138. Raulet DH. 2003. Roles of the NKG2D immunoreceptor and its ligands. Nat. Rev. Immunol. 3:78190
139. Cosman D, Mullberg J, Sutherland CL, Chin W, Armitage R, et al. 2001. ULBPs, novel MHC class I-
related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D
receptor. Immunity 14:12333
140. Champsaur M, Lanier LL. 2010. Effect of NKG2D ligand expression on host immune responses. Im-
munol. Rev. 235:26785
141. Radaev S, Rostro B, Brooks AG, Colonna M, Sun PD. 2001. Conformational plasticity revealed by the
cocrystal structure of NKG2D and its class I MHC-like ligand ULBP3. Immunity 15:103949
560 Adams Luoma

142. Li P, McDermott G, Strong RK. 2002. Crystal structures of RAE-1 and its complex with the activating
immunoreceptor NKG2D. Immunity 16:7786
143. Li P, Willie ST, Bauer S, Morris DL, Spies T, Strong RK. 1999. Crystal structure of the MHC class I
homolog MIC-A, a T cell ligand. Immunity 10:57784
144. Li P, Morris DL, Willcox BE, Steinle A, Spies T, Strong RK. 2001. Complex structure of the activating
immunoreceptor NKG2D and its MHC class Ilike ligand MICA. Nat. Immunol. 2:44351
145. Muller S, Zocher G, Steinle A, Stehle T. 2010. Structure of the HCMV UL16-MICB complex elucidates
select binding of a viral immunoevasin to diverse NKG2D ligands. PLoS Pathog. 6:e1000723
146. Chalupny NJ, Rein-Weston A, Dosch S, Cosman D. 2006. Down-regulation of the NKG2D ligand
MICA by the human cytomegalovirus glycoprotein UL142. Biochem. Biophys. Res. Commun. 346:17581
147. Wills MR, Ashiru O, Reeves MB, Okecha G, Trowsdale J, et al. 2005. Human cytomegalovirus encodes
an MHC class Ilike molecule (UL142) that functions to inhibit NK cell lysis. J. Immunol. 175:745765
148. Steinle A, Li P, Morris DL, Groh V, Lanier LL, et al. 2001. Interactions of human NKG2D with its
ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics 53:27987
149. McFarland BJ, Strong RK. 2003. Thermodynamic analysis of degenerate recognition by the NKG2D
immunoreceptor: not induced t but rigid adaptation. Immunity 19:80312

150. McFarland BJ, Kortemme T, Yu SF, Baker D, Strong RK. 2003. Symmetry recognizing asymmetry:
analysis of the interactions between the C-type lectin-like immunoreceptor NKG2D and MHC class
Ilike ligands. Structure 11:41122
151. Spreu J, Stehle T, Steinle A. 2006. Human cytomegalovirus-encoded UL16 discriminates MIC molecules
by their 2 domains. J. Immunol. 177:314349
152. Revilleza MJ, Wang R, Mans J, Hong M, Natarajan K, Margulies DH. 2011. How the virus outsmarts
the host: function and structure of cytomegalovirus MHC-I-like molecules in the evasion of natural killer
cell surveillance. J. Biomed. Biotechnol. 2011:724607
153. Cretney E, Degli-Esposti MA, Densley EH, Farrell HE, Davis-Poynter NJ, Smyth MJ. 1999. m144, a
murine cytomegalovirus (MCMV)-encoded major histocompatibility complex class I homologue, confers
tumor resistance to natural killer cell-mediated rejection. J. Exp. Med. 190:43544
154. Yang Z, Bjorkman PJ. 2008. Structure of UL18, a peptide-binding viral MHC mimic, bound to a host
inhibitory receptor. Proc. Natl. Acad. Sci. USA 105:10095100
155. Natarajan K, Hicks A, Mans J, Robinson H, Guan R, et al. 2006. Crystal structure of the murine
cytomegalovirus MHC-I homolog m144. J. Mol. Biol. 358:15771
156. Mans J, Natarajan K, Balbo A, Schuck P, Eikel D, et al. 2007. Cellular expression and crystal structure
of the murine cytomegalovirus major histocompatibility complex class Ilike glycoprotein, m153. J. Biol.
Chem. 282:3524758
157. Adams EJ, Juo ZS, Venook RT, Boulanger MJ, Arase H, et al. 2007. Structural elucidation of the
m157 mouse cytomegalovirus ligand for Ly49 natural killer cell receptors. Proc. Natl. Acad. Sci. USA
104:1012833
158. Samarakoon A, Chu H, Malarkannan S. 2009. Murine NKG2D ligands: double, double toil and trouble.
Mol. Immunol. 46:101119

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Annual Review of
Contents Immunology
Volume 31, 2013
Years in Cologne
Klaus Rajewsky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
The Biology of Recent Thymic Emigrants

Pamela J. Fink p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p31
Immunogenic Cell Death in Cancer Therapy
Guido Kroemer, Lorenzo Galluzzi, Oliver Kepp, and Laurence Zitvogel p p p p p p p p p p p p p p p p p51
Recognition of Bacteria by Inammasomes
Jakob von Moltke, Janelle S. Ayres, Eric M. Kofoed, Joseph Chavarra-Smith,
and Russell E. Vance p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p73
The Immunology of Fibrosis
Georg Wick, Cecilia Grundtman, Christina Mayerl, Thomas-Florian Wimpissinger,
Johann Feichtinger, Bettina Zelger, Roswitha Sgonc, and Dolores Wolfram p p p p p p p p p 107
Memory T Cell Subsets, Migration Patterns, and Tissue Residence
Scott N. Mueller, Thomas Gebhardt, Francis R. Carbone, and William R. Heath p p p p p 137
Control of Human Viral Infections by Natural Killer Cells
Stephanie Jost and Marcus Altfeld p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 163
Functional T Cell Immunodeciencies (with T Cells Present)
Luigi D. Notarangelo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 195
Controlling Natural Killer Cell Responses: Integration of Signals for
Activation and Inhibition
Eric O. Long, Hun Sik Kim, Dongfang Liu, Mary E. Peterson,
and Sumati Rajagopalan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 227
Metabolic Regulation of T Lymphocytes
Nancie J. MacIver, Ryan D. Michalek, and Jeffrey C. Rathmell p p p p p p p p p p p p p p p p p p p p p p p p 259
Mesenchymal Stem Cell: Keystone of the Hematopoietic Stem Cell Niche
and a Stepping-Stone for Regenerative Medicine
Paul S. Frenette, Sandra Pinho, Daniel Lucas, and Christoph Scheiermann p p p p p p p p p p p 285
Interleukin-4- and Interleukin-13-Mediated Alternatively Activated
Macrophages: Roles in Homeostasis and Disease
Steven J. Van Dyken and Richard M. Locksley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317
Brain-Reactive Antibodies and Disease
B. Diamond, G. Honig, S. Mader, L. Brimberg, and B.T. Volpe p p p p p p p p p p p p p p p p p p p p p p p 345
v
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Immunology of the Maternal-Fetal Interface

Adrian Erlebacher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 387
Regulation of Ligands for the NKG2D Activating Receptor
David H. Raulet, Stephan Gasser, Benjamin G. Gowen, Weiwen Deng,
and Heiyoun Jung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 413
Pathways of Antigen Processing
Janice S. Blum, Pamela A. Wearsch, and Peter Cresswell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 443
The Immune Response in Tuberculosis
Anne OGarra, Paul S. Redford, Finlay W. McNab, and Chloe I. Bloom,

Robert J. Wilkinson, and Matthew P.R. Berry p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 475
The Adaptable Major Histocompatibility Complex (MHC) Fold: Structure
and Function of Nonclassical and MHC Class ILike Molecules

Erin J. Adams and Adrienne M. Luoma p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 529
The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and
Their Subsets in the Steady State and the Inamed Setting
Miriam Merad, Priyanka Sathe, Julie Helft, Jennifer Miller, and Arthur Mortha p p p 563
T CellMediated Host Immune Defenses in the Lung
Kong Chen and Jay K. Kolls p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 605
Human Hemato-Lymphoid System Mice: Current Use and Future Potential
for Medicine
Anthony Rongvaux, Hitoshi Takizawa, Till Strowig, Tim Willinger,
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Signaling by the Phosphoinositide 3-Kinase Family in Immune Cells
Klaus Okkenhaug p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 675
Broadly Neutralizing Antiviral Antibodies
Davide Corti and Antonio Lanzavecchia p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 705
Molecular Control of Steady-State Dendritic Cell Maturation and Immune
Homeostasis
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An online log of corrections to Annual Review of Immunology articles may be found at

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The Adaptable MHC Fold. Structure and Function of Nonclassical and MHC Class I-Like Molecules.

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Annual Reviews content online,

Function of Nonclassical and

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MHC Class ILike Molecules

Annu. Rev. Immunol. 2013. 31:52961 Keywords

INTRODUCTION functions, including as ligands for the activating

that anchor the I and class II types, serve to present peptides of

rived from a single polypeptide chain (heavy

530 Adams Luoma

proteins. Peptides are bound between the two Human Mouse

differs in each MHC molecule and determines HLA-B

peptide (MHCp) complexes can initiate T cell M10.2

www.annualreviews.org Nonclassical and MHC-Like Proteins 531

a ds * bootstrap values < 50%

532 Adams Luoma

www.annualreviews.org Nonclassical and MHC-Like Proteins 533

Qa-1 CD94/ Qa-2

534 Adams Luoma

receptor on HLA-E spans the peptide-binding

www.annualreviews.org Nonclassical and MHC-Like Proteins 535

as playing a role in embryonic development. disulde-linked dimer in solution and on the

by HLA-E and Qa-1, although the repertoire

with HLA-G expression in the placenta (34).

536 Adams Luoma

www.annualreviews.org Nonclassical and MHC-Like Proteins 537

538 Adams Luoma

a TL HLA-A2 b T22 HLA-A2 c M10 HLA-A2

Approximately 0.12% of murine T cells M afnity, has a histidine in this interface,

www.annualreviews.org Nonclassical and MHC-Like Proteins 539

M10: A Pheromone Detector?

M10 represents one of the more interesting Lipid Metabolism

for nonimmune functions. It is expressed as a

540 Adams Luoma

Iron Uptake HFE in the mouse results in a decrease in the

www.annualreviews.org Nonclassical and MHC-Like Proteins 541

542 Adams Luoma

below. Phylogenetically related homologs microbial-derived lipids, it is understandable

structures need further elucidation. thymocytes (97). In particular, Langerhans

widespread expression pattern, with most B

www.annualreviews.org Nonclassical and MHC-Like Proteins 543

a CD1a-presented lipids b CD1b-presented lipids

c CD1d-presented lipids -Galacto-

544 Adams Luoma

for T cell recognition, as discussed above, and

www.annualreviews.org Nonclassical and MHC-Like Proteins 545

F ruler (Figure 9) (109). The F pocket is straight

ability in ligand structures that occupy this

546 Adams Luoma

www.annualreviews.org Nonclassical and MHC-Like Proteins 547

EPCR: A CD1-Like Molecule

548 Adams Luoma

revealed a hydrophobic binding groove capable CD1d-LPC

www.annualreviews.org Nonclassical and MHC-Like Proteins 549

THE NKG2D LIGANDS: mology to ULBP1 and 2, additional members

ulatory ligands for the NKG2D receptor (138)

550 Adams Luoma

www.annualreviews.org Nonclassical and MHC-Like Proteins 551

ligand surface. Y152, M184, and Y199 in hu-

552 Adams Luoma

HLA-A2 UL18 m144 m153 m157

www.annualreviews.org Nonclassical and MHC-Like Proteins 553

554 Adams Luoma

F ruler (Figure 9) (109). The F pocket is straight