Professional Documents
Culture Documents
Editors: Shils, Maurice E.; Shike, Moshe; Ross, A. Catharine; Caballero, Benjamin;
Cousins, Robert J.
become more and more restricted in the number of cell types that they can produce.
These cells are spoken of as being committed to a given cell lineage or range of
lineages.
In the early fetal development of the mouse, nucleated erythrocytes with embryonic
forms of hemoglobin appear in the yolk sack. These cells are incapable of producing
other hematopoietic lineages (9), but they may have a greater lineage potential when
injected directly into a newborn liver (10). Generation of all blood cell types including
lymphocytes is initiated at about 9 to 10 days post coitus in the splanchopleural aorta-
gonad-mesenepheros (Sp/AGM) (11). These cells are capable of long-term repopulation
of lethally irradiated adults giving rise to all the lineages of blood cells (12,13). These
multipotent cells then colonize the liver at about 11 days post coitus, and hematopoiesis
takes place there until shortly before birth. Just before birth, the spleen becomes the
primary site for hematopoiesis. Thereafter, hematopoiesis in the spleen gradually
declines to very low levels over 2 to 4 weeks while concomitantly this process increases
in the bone marrow.
B Cells
Advances in our understanding of B-cell development and function have recently been
described (14). The intermediate stages that stem cells pass through on their way to
becoming B cells have been described in terms of expression of a variety of cell-surface
and internal proteins, some with known functions and others whose roles are still
unclear. The B-cell development pathway is defined by isolation and culture of
intermediate stages and documentation of their progression to later stages. For example,
uncommitted HSCs generate more committed progeny expressing interleukin (IL)-7R
that, in turn, produce B-lineagerestricted cells expressing CD45R/B220 (CD is
cluster of differentiation), but not CD19, which is characteristic of later B-cell stages.
Thus, a scheme can be constructed for B-cell development on which the influence of
mediators such as transcription factors, cytokines (Table 43.1), and gene mutations can
be tested. The appearance of processes known to occur during B-cell development such
as rearrangement of the D-J (diversity-joining) region and immunoglobulin (Ig) heavy-
chain expression can also be incorporated into this scheme (14). As hematopoiesis is
initiated, the earlier stages of the B-cell lineage predominate, then successively later
stages of B-cell development predominate until birth (15).
B cells produced in the liver during gestation are distinctly different in some respects
from those produced in the bone marrow of the adult mouse. Fetal cells lack the enzyme
terminal deoxynucleotide transferase (TdT) (16), which catalyzes nontemplate-
dependent addition of nucleotides at the D-J and V-D (variable-diversity) junctions of
the Ig heavy-chain gene locus (17).
In the adult mouse, the bone marrow is the primary source of B cells. Bone marrow
contains a mixture of cells at various stages of commitment to the blood cell lineages.
The least committed cells, capable of producing any of the blood cells, are termed
lineage negative HSCs. This fraction makes up less than 5% of HSCs or
1/30,000th of the bone marrow cells. When successively transferred into recipient mice
devoid of nucleated blood cell precursors these cells are capable of repopulating all
blood cell lineages in two successive transfers. Another population of HSCs, termed
common lymphoid progenitor (CLP) cells, can generate B, T, natural killer (NK), and a
subset of dendritic cells (DCs). These cells lack a panel of lineage markers but express
the IL-7R chain and lower levels of c-kit and make up about 1/3000th of bone
marrow cells.
Distinct stages of B-cell development can be defined by function or phenotype.
Functionally, the earliest cells require contact with nonlymphoid adherent cells present
in bone marrow, known as stromal cells, and IL-7 for growth in culture (18), whereas
later stages can grow without cell contact but still require cytokines (19). Adhesion
molecules such as CD44 and VLA-4 that interact with hyaluronate and VCAM-1 appear
to explain at least part of the dependence on stromal cells (20). Stromal cells also
produce IL-7 (18), which is critical for proliferation. The phenotype of developing B
cells can be identified using specific surface or intracellular markers detected by the
binding of fluorescent antibodies to these markers, followed by fluorescence
microscopy or flow cytometry. Some examples are CD45Ra (T200) and RA3-6B2,
which is highly stage restricted (21). However, even these highly restricted markers can
be present on other cell types including certain stages or subsets of NK cells and DCs.
Multiparameter/multicolor flow cytometry with additional antibodies can differentiate
many of these intermediate stages (19).
After their formation in the bone marrow, B cells migrate to the spleen, where they
undergo further maturation in the red pulp; then they enter the splenic follicle region,
where they form a pool of cells that circulates from the spleen to the periphery. Cell
migration is dependent on the interaction of receptors on the cell surface with
chemokines. T-celldependent immune responses result in the formation of
anatomically distinct structures in the spleen and lymph nodes called germinal centers.
Germinal centers contain large numbers of rapidly cycling B cells, marked by their
ability to bind peanut agglutinin (PNA) and their lack of surface (s)IgD (22). Many of
these cells have a low level of expression of BCL-2 and elevated expression of FAS and
are therefore destined for apoptosis (see later) unless they receive strong B-cell receptor
(BCR) signaling (23). Lack of IgD expression results in a decrease of surface BCR
expression of at least tenfold. Cells with increased affinity for antigen generated by a
process called hypermutation arethus favored.
TABLE 43.1. CYTOKINES AFFECTED BY NUTRITIONa
CYTOKINE SOURCE TARGET FUNCTION
GM-CSF Th cells Progenitor cells Growth and differentiation of
monocytes and dendritic cell.
IL-1 Monocytes Th cells Costimulation
IL-1 Macrophages B cells Maturation and proliferation
B cells NK cells Activation
Dendritic cells various Inflammation, acute-phase
response, fever
IL-2 Th1 cells Activated T and B Growth, proliferation,
cells, NK cells activation
IL-4 Th2 cells Activated B cells Proliferation and
Macrophages differentiation
T cells IgG1 and IgE synthesis
MHC class II proliferatio.
IL-5 Th2 cells Activated B cells IgA synthesis proliferation
and differentiation.
IL-6 Monocytes Activated B cells Differentiation into plasma
Macrophages Plasma cells cells
Th2 cells Stromal cells Antibody secretion
Stem cells Various Differentiation
Acute-phase respons.
IL-7 Marrow stroma Stem cells Differentiation into
Thymus strom. progenitor B and T cells
IL-8 Macrophages Neutrophils Chemotaxis
Endothelial cell.
IL-10 Th2 cells Macrophages Cytokine production
B cells Activation.
IL-12 Macrophages Activated Tc cells Differentiation into CTL
B cells NK cells (with IL-2)
Activation.
IFN- Leukocytes Various Viral replication
MHC I expression.
IFN- Th1 cells, Various Viral replication
Tc cells, NK cells Macrophages MHC expression
Activated B cells Ig class switch to IgG2a
Th2 cells Proliferation
Macrophages Pathogen elimination.
TGF- T cells, monocytes Monocytes, Chemotaxis
macrophages IL-1 synthesis
Activated IgA synthesis
macrophages Proliferation
Activated B cells
Various
TNF- Macrophages, mast Macrophages Cell adhesion molecule and
cells, NK cells Tumor cells cytokine expression
Cell deatn.
TNF- Th1 and Tc cells Phagocytes Phagocytosis, nitric oxide
Tumor cells production, cell death
CTL, cytotoxic T lymphocyte; GM-CSF, granulocyte-macrophage colony-stimulating
factor; IFN, interferon; Ig, immunoglobulin; IL, interleukin; MHC, major
histocompatibility complex; NK, natural killer; TGF, transforming growth factor; TNF,
tumor necrosis factor.
a
Cytokines listed in bold letters are known to be affected by one or more nutrients as
indicated in the text. Italics indicates a major function of this cytokine shown to be
affected by nutrition.
Adapted from
http://www.microvet.arizona.edu/Courses/MIC419/Tutorials/cytokines.html.
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B-Cell Subsets
Distinct populations of B cells can be distinguished by their phenotype and anatomic
location (24). Immature B cells shortly after exiting the bone marrow are found in the
spleen and are membrane (m) mIgM+mIgD- cells. Whereas most of these cells are
eliminated by apoptosis with a half-life of 2 to 3 days, some of them, called
conventional or B-2 B cells, reach a longer-lived recirculating compartment in which
they have a half-life of approximately 30 days. These mature B cells, typically
mIgD++ mIgM+, comprise more than 95% of naive B cells found in the peripheral lymph
nodes and are the precursors for the T-helper (Th)celldependent B-cell responses
to most foreign protein antigens. Cells of another subset, termed B-1 B cells, are distinct
from B-2 B cells in their expression of CD5, CD11b, CD43, and high levels of sIgM
and low levels of sIgD, B220, CD21, and CD23 (25).
The origin of these B-1 B cells is uncertain; some investigators suggest that they are
derived from precursors in the fetal liver as long-lived products of a separate lineage of
B cells that emerged and stabilized during the neonatal period (26). B-1 B cells are
found in large numbers in the peritoneal and pleural cavities, where they constitute a
high percentage of total B cells, and in spleen, where they constitute a much lower
percentage of B cells. They are characterized by their ability to produce self-reactive
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to fulfill their roles in the periphery. This T-cell maturation process involves not only
downregulation of one coreceptor (CD4 or CD8) and expression of the other, but also
the expression of many other effector genes specific to the T-helper (Th, CD4+) or T-
cytotoxic (CD8+) phenotype, and suppression of those genes not needed. These effector
genes are first expressed early in the maturation process (36). Once these SP T cells
have matured, they still must receive survival signals to enable their prolonged survival.
Mature T cells finally leave the thymus in a noncoordinated fashion between 7 and 14
days after positive selection (37).
In addition to the SP CD8 and CD4 T cells are other T cells that arise during the
developmental stages. One of these is the NKT cell, a type similar to NK cells in many
ways including expression of surface markers (38). However, unlike ordinary T cells,
these NKT cells are capable of producing high levels of IL-4 and interferon- on
encountering antigen, and they therefore may be important in controlling autoimmunity
and tumors as well as infectious diseases. Most NKT cells bind the nonclassic class I
MHC relative, CD1d (39). NKT cells first appear approximately 6 days after birth in
mice and increase 12- to 14-fold by 5 to 6 weeks of age, when they comprise about 0.6
to 0.7 % of thymocytes. Although they recognize a class I MHC-type ligand, most are
CD4+ or DN.
Other types of NKT cells exist at much lower abundance and vary in their surface
markers, TCR repertoire, CD1d dependence, NK1.1 expression, and tissue localization.
Although NKT cells generally require all the genetic functions of T cells and depend
on the presence of pT (40), they probably represent a separate lineage because several
mutations that affect their development do not have much effect on conventional T-
cell development, and vice versa (41,42). These NKT cells are capable of producing a
combination of Th-2 cytokines and NK cell-like cytolytic functions, and, like NK cells,
their prodution depends on IL-15/IL-15R and lymphotoxin (LT)/LTR signals (40,43).
Another type of T cells, termed regulatory T (Treg) cells and which are potent
suppressors of organ-specific autoimmunity, has also been identified (44). These cells
constitute about 5% of mature thymic CD4 SP cells (45). Regulatory T cells appear to
arise from CD4 SP cells during the time of negative selection and maturation in the
thymus and require IL-2 for their development or survival or both (46). These cells
express the transcription factor Foxp3 (Scurfin), which antagonizes conventional T-cell
activation responses. Mutant mice lacking this gene develop lethal autoimmunity (47).
Deficiency of certain nutrients such as folate and other vitamins causes selective T-cell
dysfunction and disruption of the maturation process.
INNATE AND ADAPTIVE IMMUNITY
Innate immunity is mediated by monocyte/macrophage cell lineages. During infection,
these cells alone are actively involved in clearing infectious agents. Monocytes can
differentiate into multiple effector cell types. Macrophages are important for bacterial
clearance, glial cells are important for brain function, osteoclasts are important in bone
remodeling, and Kupffer cells are important in liver homeostasis.
Adaptive or acquired immunity refers to antigen-specific immunity that develops over a
longer period. It involves humoral and cell-mediated immunity produced by B and T
lymphocytes, respectively. Adaptive immunity enables the host to respond to specific
pathogenic organisms and to retain memory of those organisms for subsequent
responses.
The generation of an immune response involves a series of interactions between
lymphocytes and mononuclear cells, including cell-cell communications, generation of
immunoreactive molecules, mitotic division, Ig synthesis and secretion, and expression
of several cell-surface markers not found on resting lymphocytes. An effective immune
response requires balanced functioning of T-helper (CD4) and T-cytotoxic (CD8)
subsets of thymic-dependent T lymphocytes, antibody-producing B lymphocytes (Ig+),
macrophages, and NKs, and the interplay of various enhancing or inhibiting cytokines.
B-Cell Signaling and Activation
Signaling Pathways
As one component of the adaptive immune response, humoral immunity provides
immediate and long-term protection from a wide variety of infectious agents. Infection
results in signaling and recruiting antigen-specific B cells, leading to an adaptive
immune response. B-cell signaling and activation have recently been fully described
(48). The BCR signaling complex involves a membrane bound form of Ig (mIg), which
interacts with and binds specific antigens, and a noncovalently associated heterodimer
composed of Ig- (CD79a) and Ig- (CD79b), which acts as a signaling subunit for the
BCR complex (49). The / heterodimer is associated with the heavy-chain constant
region of the mIg in a 1:1 ratio (50). These complexes segregate in the membrane as
BCR oligomers in an Ig isotype-specific manner. The / heterodimers associated with
all classes of mIg are the same except for differences in glycosylation (51). Both Ig-
and Ig- contain a region in their cytoplasmic tail region referred to as an immune-
receptor tyrosine-based activation motif (ITAM), characterized by six conserved amino
acid residues (52,53). Such motifs are also found on the cytoplasmic regions of TCR
signaling components, certain Fc receptors, and CD22. Cross-linking of these receptors
induces tyrosine kinase activity and the mobilization of intracellular calcium (53). These
motifs function as one means of communicating a BCR signaling event into one or
more of several intracellular signaling pathways. The / heterodimer is essential for
B-cell development from precursors (54), and the mIg
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extracellular, with only five amino acid residues in the cytoplasmic domain, which is
insufficient to couple them to signal transducers in the cytoplasm. This signal-
transducing function is supplied by the CD3 and chain components of the TCR
complex (76). These chains contain the ITAM sequences that are typical of many
different receptors on several different types of cells (76).
The mechanism of signaling from the CD3 and chains after antigen has bound to the
/ chains is not well understood. Some evidence suggests a cross-linking or
dimerization model, whereas other evidence argues for allosteric changes (77). There is
also a suggestion that the CD3 and chains may allow other cell-surface molecules
such as CD2, CD4, or CD8 to interact with the TCR to form a larger receptor complex
(78). Within seconds after binding of MHC-associated antigen to the TCR, tyrosines on
the ITAMs are phosphorylated (79). This phosphorylation is mediated by protein
tyrosine kinases (PTKs) of the Src and Syk families and persists for hours (80). These
PTKs, in turn, phosphorylate other proteins and activate effector molecules downstream
through the MAPK and other signaling pathways. This cascade of events results in the
stimulation of cytokine production and the appearance of new cell-surface molecules
that facilitate the role of the T cell in recruiting and activating B cells (i.e., humoral
immunity) and promoting destruction of invading organisms (i.e., cell-mediated
immunity) (81,82).
Protein phosphorylation is influenced not only by phosphorylases but also by
phosphatases. Phosphatases are expressed at high levels on all hematopoietic cells, with
the exception of mature erythrocytes, and catalyze the hydrolysis of phosphate bonds,
resulting in dephosphorylation. T cells possess several phosphatases such as the
membrane-bound CD45 (leucocyte common antigen or T200), CD148, PTPase
(LRP), and the cytosolic T-cell phosphatases, PEP, SHP-1, and SHP-2 (83). The best
characterized of these is CD45. Various isoforms of CD45 are expressed differentially
according to the cell's maturity and activation state (84). Studies with CD45 deficient
cells suggest that its target may be the negative regulatory site of Lck. Removal of a
phosphate from this site results in a conformational change in Lck that allows it to
become activated by transautophosphorylation of tyrosine in its activation loop (85).
PTPases can also remove phosphate from such activation sites and thereby negatively
regulate signaling activity. After the successful completion of the immune response,
excess T-cell populations are eliminated by apoptosis, as discussed in the following
section.
Programmed Cell Death (Apoptosis)
As has been recently described in detail (86), an important part of the flexibility
essential to the adaptive immune system and control of self-tolerance is regulation of
the number and specificity of immune cells by survival or death (87,88,89,90). This is
accomplished by expression of certain proteins within or on the surface of the cells that
initiate a sequence of events leading to the death of the cell. This type of cell death has
been named apoptosis, from the Greek meaning to fall off, as in leaves falling
from a tree during the annual dormant phase (91). This term is used to distinguish this
natural programmed death from the accidental or toxin-induced death, termed necrosis.
This term has become associated with a specific pathway involving the action of
proteases called caspases and a distinctive morphology of the cells as they progress
through the various stages of apoptosis. Molecular programs have also been defined that
result in necrotic death of cells (92).
At several points during the development of lymphocytes from stem cells, as discussed
earlier, large numbers of cells bearing receptors of varying selectivity are produced, and
then those that are useful are selected to survive, whereas the remaining cells are
eliminated by apoptosis. As one example, during the development of thymocytes, the
TCR genes become rearranged in a somewhat random fashion. Those rearrangements
that yield receptors with a useful range of affinity for the MHC-antigen complex result
in survival of the respective T cells, and those that do not result in cell death. The
selection of these cells is based on the strength of the TCR signal. If there is no TCR
stimulation, the cells will undergo what has been termed death by neglect (93). This
effectively eliminates cells whose TCR rearrangement has not resulted in MHC-antigen
recognition. In T cells receiving a low level of TCR stimulation, this death by neglect is
antagonized, and this event is called positive selection. Thus, T cells with a minimum
threshold level of MHC recognition are selected for survival (94). Those T cells whose
TCR signal is excessively strong will receive a proapoptotic signal that is termed
negative selection. Negative selection prevents the appearance of strongly autoreactive
lymphocytes in the periphery (93).
In the periphery, it is necessary to limit the proliferation of mature thymocytes that have
been stimulated and performed their function. This regulation must, however, be
antigen specific because some T cells may be undergoing expansion in response to an
invasion at the same time that others, responding to a different antigen, have
accomplished their purpose and need to be checked. The term propriocidal
regulation is used to refer to the mechanisms that have been developed to
accomplish this purpose. This apoptosis is triggered by the level of cell cycling and the
level of antigen restimulation (89). Cell death can occur actively by antigen-stimulated
apoptosis or passively by lymphokine (survival signal) withdrawal. Initiation of active
cell death requires more than activation and proliferation of T cells. Strong
restimulation by antigen while in the activated state after the initial antigen stimulation
is required (95). Thus, the initial response to an invading antigen is not compromised,
but continued stimulation by the same antigen, which is most likely to occur with self-
antigens, is prevented by eliminating these cells. The
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correlated with reduced nitric oxide production by macrophages in vitro and reduced
TNF- production in vivo (117).
Vitamin A.
Retinoic acid has been shown to delay the onset of autoimmune disease in mice (118),
and it may even be beneficial in viral infections because retinoic acid can inhibit human
immunodeficiency virus (HIV) replication in macrophages in vitro (119). Retinoic acid
may also be important in generating monocytes from progenitors in the bone marrow
(119) and subsequently in assisting the differentiation of monocytes into macrophages
(120) or DCs (121).
Vitamin D.
Studies in vitamin D receptor knockout mice have revealed that vitamin D is important
in macrophage functions such as chemotaxis, although phagocytosis was normal, but it
does not appear to play a role in the generation of monocytes (122). Treatment of
macrophages with vitamin D in vitro enhanced the phagocytic uptake of bacteria (123).
Vitamin D is also known to regulate bone resorption and increase blood calcium levels
by regulating osteoclast activity, a cell type of the monocyte/macrophage cell lineage
(124).
Vitamin E.
A human study has shown that vitamin E supplementation can reduce the risk of
respiratory tract infections in the elderly (125). The macrophage is the likely target
(126). Vitamin Edependent regulation of macrophage function may also be
important in the development of heart disease (127). Vitamin E supplementation
prevented macrophage accumulation in the aorta of rabbits fed a diet high in saturated
fat and cholesterol (atherogenic diet) (128). However, some vitamin E isomers are
cytotoxic to macrophages and other cell types in vitro (129), a finding suggesting that
caution in the use of supplemental vitamin E is warranted.
Zinc.
Zinc has been shown to regulate cytokine gene expression selectively in macrophages.
Zinc increased the expression of macrophage colony-stimulating factor (130) and
decreased the expression of TNF-, IL-1, and IL-8 genes (131).
Selenium.
Selenium reduced the production of nitric oxide by activated murine macrophages
(132), and selenium deficiency increased nitric oxide production in a macrophage-like
cell line (133).
Natural Killer Cells
Most of the studies examining the impact of nutrients on NK cell activity have centered
on how nutrients affect the ability of NK cells to kill tumor cells.
Vitamin A.
A lack of vitamin A, even marginal deficiency, resulted in a lower number and
percentage of NK cells in both young and old rats (134), concomitant with reduced
cytolytic activity in standard NK cell assays. These changes were reversed by retinoic
acid. Aging vitamin Amarginal rats with low NK cells had, conversely, an increased
number of NKT cells, associated with reduced CD4+ T cells and a lower CD4:CD8
ratio (135). Feeding a diet with elevated levels of vitamin A resulted in increased NK
and reduced NKT cells, compared with age-matched controls, a finding indicating
reciprocal regulation of these cell types by vitamin A (135). In vitamin Adeficient
mice (136) and rats with low NK cells (137), blood granulocytes were significantly
increased.
n-3 Fatty Acids.
Both increases and decreases in NK cell activity have been observed in human and
rodent studies in which n-3 polyunsaturated fatty acids have been fed (138). These
differences are likely the result of the modulating impact of other factors. For example,
some n-3 fatty acids were more potent than others at inhibiting human NK cell activity
(139), and the ratio of polyunsaturated to saturated fatty acid in the diet was a
determinant of whether NK cell activity was increased or decreased in rodents (140).
Conjugated Fatty Acids.
Supplementing healthy men with CLA isomers was tested on NK cell function, but it
was without an effect (141).
Zinc.
Zinc supplementation at a level to return plasma zinc status to physiologic levels
(1216 umol/L) resulted in restoration of normal NK cell function. Physiologically
relevant levels of zinc supplementation in elderly persons resulted in increased NK cell
activity (142). When zinc was added to NK cells in vitro at concentrations higher than
normal physiologic levels, NK cell activity was inhibited (143). Thus, too much zinc
may have a similar negative effect as zinc deficiency. An important mechanism by
which zinc increases NK cell activity is by increasing the interaction between NK cell
receptors and MHC I receptors on target cells (144).
Dendritic Cells
The literature examining the impact of nutrients on DC function is limited, but it has
been expanding rapidly as it has become appreciated that DCs may serve as the key link
between innate and adaptive immunity (145).
Vitamin A.
Vitamin A may be important in regulating the production of a sufficient number of DCs.
Retinoic acid added in vitro helped to induce the differentiation of murine myeloid
(progenitor) bone marrow cells into the DC phenotype (146) and, similarly in human
cells, of peripheral blood mononuclear cells of the DC phenotype (147). In T cells, the
effects of retinoic acid favored the production of IL-12 (121), which would increase a
cell-mediated type of immune response by T cells.
Vitamin D.
Vitamin D and several analogs have been shown to inhibit the ability of DCs to
stimulate naive T cells (148). This inhibitory effect may be specific to T-cell stimulation
for the generation of a Th-1 type of response, because DCs cultured with vitamin D
exhibited increased IL-10 secretion, which would favor an antibody-mediated (Th-2)
response (149). This specific downregulation of cell-mediated immunity may be
important in regulating
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responses but ultimately may prevent appropriate antibody responses as well (188). In
children with very low plasma retinol levels, inflammatory cytokine production was
elevated as compared with that in children without severe deficiency (189). The ability
of vitamin A to boost immunity in mice may be indirect by increasing APC function
(190). Mechanistically, retinoic acid increased T-cell function by increasing IL-2R
expression (191) and IL-2 secretion (192). In addition, T-cell functioning may be
improved through alterations in T-cell development in the thymus (193). Alternatively,
as alluded to earlier, retinoic acid may regulate T-cell function indirectly by altering
MHC expression on APCs or other target cells (194). Vitamin A supplementation may
not have a benefit in all infectious diseases because vitamin A supplementation was
shown to have no impact on herpes simplex virus infectivity (195) or HIV disease
progression (196).
Vitamin D.
Vitamin D can exert antiinflammatory effects leading to suppressed experimental
autoimmune encephalitis, systemic lupus erythematosus, type 1 diabetes (197,198),
inflammatory bowel disease (198), and murine allergic airway disease (199). Several
different analogs of vitamin D have been developed as immunomodulators as well
(200). The immunoregulatory properties of vitamin D may be exerted indirectly by
altering accessory cell function, as in DCs (150), or by directly altering T-cell function.
Vitamin D has been shown to modulate integrin receptor-mediated T-cell homing (201)
and to repress CD95 ligand receptor expression (202), which may inhibit T-cell
apoptosis. In primary T-cell cultures, vitamin D inhibited Th-1 cytokine production but
did not alter Th-2 cytokine production in CD4 cells (203), whereas in other
experimental cultures vitamin D increased both Th-1 and Th-2 cytokine production
(204). The discrepancy in some of these studies may be explained by observations
showing that the effect of vitamin D on T-cell function is dependent on the
differentiation and activation status of the T cell (205). Although CD8 T cells have the
highest expression of the vitamin D receptor, CD8 T cells are not needed for vitamin D
to inhibit experimental autoimmune encephalomyelitis (206). Vitamin D may also have
a direct effect on B cells because recent evidence indicates that IgE production in
activated B cells is inhibited (207). Recently, heterogeneous nuclear ribonucleoprotein
has been shown to inhibit vitamin Dinduced gene expression (208), which may
explain why some T cells are resistant to immunoregulation by vitamin D.
Vitamin E.
Vitamin E (-tocopherol) is best known for its antioxidant capability and for protecting
the immune system against oxidative damage. Examples include protecting T cells from
lead-induced toxicity (209) and B cells from hydrogen peroxide promoted viral
transformation (210). Vitamin E is thought to be important in downregulating allergic
inflammation by suppressing IL-4 expression (211) and may prevent pathologic
deletion of T cells by blocking apoptosis (212). Blocking apoptosis may be an important
mechanism in the ability of vitamin E to increase the proliferation of naive T cells in
aged mice (213). Memory T cells, which become predominant during aging, were not
affected by vitamin E (213), and this finding may explain why adding vitamin E had no
apparent effect in bulk aged T-cell cultures in vitro (214). A unique application of
taking advantage of vitamin E's immunoregulatory properties is seen in coating a
hemodialyzer with vitamin E; this abated the spontaneous release of IL-4 and IL-10 by
the CD4+ T cells and of IL-12 and IL-18 by the peripheral blood mononuclear cells of
patients undergoing dialysis (215).
Zinc.
Two reviews provide an excellent detailed explanation of the role of zinc on T-
celldependent immune function (216,217). In general, zinc deficiency is associated
with a decline in most aspects of immune function. Zinc deficiency renders people more
susceptible to infections. Conversely, zinc supplementation in humans has shown
benefit in immune responses to bacterial (218) and viral infections (219). However, zinc
could also have deleterious effects on immune function because it can also serve to
promote oxidative damage. In a study in healthy persons, zinc supplementation did not
have a negative effect on T-cell function in general (220). This is especially important
because zinc can modulate gene expression in the thymus, where T cells mature
(131,221), and thereby affect subsequent T-cell production (222).
Selenium.
Most research on selenium and T-cell function has examined selenium deficiency (223).
Selenium appears beneficial in Th-1type immune responses against intracellular
pathogens (224). Evidence from a clinical study suggests that increasing selenium
intake may be beneficial in polioviral infections in humans (225).
CONCLUDING SUMMARY
Nutritional status has been found to affect all the major cell lineages involved in
immune function. Food restriction has been reported to decrease inflammation and
preserve immune function during aging, but it has also been reported to decrease
resistance to sepsis in young animals. n-3 and conjugated fatty acids such as CLA have
been shown to decrease inflammation and to influence the production of a number of
cytokines and prostaglandins. The fat-soluble vitamins A, D, and E have many effects
on the immune system, ranging from the maturation of various cell lineages to cell
functions such as phagocytosis and apoptosis. These various effects may be mediated
through alterations of cytokine and receptor expression. The trace elements zinc and
selenium are also known for their effects on immune cells. Adequate zinc levels are
necessary for NK cell function, and zinc regulates cytokine expression in macrophages
and enhances T-cell function. The effects of selenium are less well characterized and
appear most closely to be related to its antioxidant capacity.
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Acknowledgments
We wish to acknowledge support from National Institutes of Health grants AG023648,
AG014541, and AG020239 (G.F.) and AG020651 (C.A.J.) for our work. We are also
grateful to Dr. Catharine Ross for her helpful suggestions.
1
Abbreviations
APC
antigen-presenting cell
BCR
B-cell receptor
CD
cluster of differentiation
CLA
conjugated linoleic acid
DC
dendritic cell
DHA
docosahexaenoic acid
DP
double-positive (cell)
EPA
eicosapentaenoic acid
HIV
human immunodeficiency virus
HSC
hematopoietic stem cell
Ig
immunoglobulin
IL
interleukin
ITAM
immunomodulatory tyrosine-based activating motif
ITIM
immunomodulatory tyrosine-based inhibitory motif
MHC
major histocompatibility complex
NK
natural killer (cell)
SP
single-positive (cell)
TCR
T-cell receptor
Th
T-helper (cell)
TNF
tumor necrosis factor
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SELECTED READINGS
Abbas A, Lichtman A, Pober J, eds. Cellular and Molecular Immunology. Philadelphia:
WB Saunders, 1991.
Calder PC, Gill HA, Field CJ, eds. Nutrition and Immune Function. Cambridge, MA:
CAB International, 2002.
Gershwin ME, Keen CL, German JB, eds. Nutrition and Immunology: Principles and
Practice. Totowa, NJ: Humana Press, 2000.
Hughes DA, Bendich A, Darlington LG, eds. Diet and Human Immune Function.
Totowa, NJ: Humana Press, 2004.
Paul WE, ed. Fundamental Immunology. 5th ed. Philadelphia: Lippincott Williams &
Wilkins, 2003.