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Modern Nutrition in Health and Disease, 10th Edition; Nutrition in

Integrated Biologic Systems; 43 - Nutrition and the Immune System

Editors: Shils, Maurice E.; Shike, Moshe; Ross, A. Catharine; Caballero, Benjamin;
Cousins, Robert J.

Nutrition and the Immune System


Gabriel Fernandes
Christopher A. Jolly
Richard A. Lawrence

INTERACTION OF NUTRIENTS AND THE IMMUNE SYSTEM


The sciences of nutrition and immunity are intimately linked to each other and are
currently facilitating the understanding of cellular and molecular mechanisms involved
in maintaining a healthy and disease-free life span. In recent years, nutrition research
and immunologic studies have been extremely valuable in understanding human growth
and development, maintenance of proper health, disease prevention, and disease control.
The nutrients in foods are chemical components that (a) provide fuel and energy for
regulation and maintenance of physiologic processes and (b) promote growth and repair
of body tissues. The role of nutrition in the immune system was studied initially, in the
early 1970s, by Fernandes and Good and colleagues (1,2,3,4), Walford and associates
(5,6), and Fraker and colleagues (7). Since then, numerous investigations on the
influence of both macronutrients and micronutrients on both cellular and humoral
immunity have been conducted, mostly in rats and mice. The immune system requires
nutrients to produce and distribute normal healthy immune cells throughout the body
(hematopoiesis, see next section), to combat invasive pathogenic microorganisms
(innate and adaptive immunity), and to discriminate between self- and nonself-antigens
(adaptive immunity). Collectively, these functions serve to protect the integrity of the
host organism. The immune system is a highly intricate, delicately regulated network of
cells that are intimately involved in both innate and adaptive immune responses. The
tools of immunology and molecular biology provide a resourceful approach to
investigate the role of various dietary components in maintaining the optimal function
of immune cells, not only to prevent infection, but also possibly to protect against the
occurrence of cardiovascular disease, cancer, age- and autoimmune-related disorders,
and acquired immunodeficiency syndrome in humans.
The immune system is fully equipped to recognize and to respond constantly, not only
to viral and other infectious agents, but also to a large number of invading foreign
antigens. New sources of antigens are regularly infused into the body by absorption of a
variety of common food products and liquids. Besides allergenic food substances,
insults from carcinogens, food preservatives (e.g., nitrate and nitrite), or polycyclic
aromatic hydrocarbons ingested in charred foods, vegetables, or fruits may initiate the
activation of immune responses (8). In this chapter, we provide a concise review of
recent advances in understanding innate and adaptive immunity including B- and T-cell
development, signaling, activation, and the demise of immune cells by apoptosis. The
second half of the chapter focuses on the role of selected key nutrients in innate and
adaptive immunity.
DEVELOPMENT OF THE IMMUNE SYSTEM (HEMATOPOIESIS)
All blood cells are derived from hematopoietic stem cells (HSCs) by differentiation.
Populations of cells at various stages in development of the different branches are
present in all tissues supporting hematopoiesis. As the progeny of these cells pass
through progressive stages, they
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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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antibodies to branched carbohydrates, glycolipids, and glycoproteins including


phosphorylcholine, phosphatidylcholine, the Thy-1 glycoprotein, and bacterial cell wall
constituents (27). These so-called natural autoantibodies are not pathogenic, but their
biologic function is not known for certain. At least some of them are thought to be
important for clearance of senescent cells or proteins, and some may provide initial
immunity to common bacterial or viral pathogens (28). One of the major roles of B cells
is to produce various Igs that are essential for eliminating infection. The production of
antigen-specific antibodies by B cells is central to successful vaccination.
Another B-cell subset found in the periphery comprises the memory B cells. Memory B
cells are produced during T-celldependent immune responses. These cells are very
long-lived or self-regenerating, and they probably only arise from antigen-stimulated
follicular B cells in the germinal center. Their Ig genes are isotype switched (IgM to
IgG+), and these B cells continue to express CD45R/B220 and a low surface density of
BCR (29). When they are challenged with a previously encountered antigen, memory B
cells are capable of rapid, high-level production of high-affinity antibodies (30). This
memory or recall response is also a hallmark of successful vaccination and provides
long-term protection to the vaccinated host.
T Cells
Unlike B cells, most circulating T cells develop in the thymus (Fig. 43.1). Bone marrow
cells entering the thymus from the circulation undergo a course of differentiation and
selection to become T cells. Advances in our understanding of this process have
recently been fully described (31). This cycle occurs continuously from about the
midgestational period throughout adulthood in mammals. Some T cells also develop in
the intestinal epithelium but do not circulate outside of the intestines. T cells that
develop in the thymus are also rigorously screened there to eliminate T cells expressing
useless or potentially harmful T-cell receptors (TCRs) in a process that has been labeled
repertoire selection. The cells entering the thymus from the bone marrow are called
DN1 or TN1 cells, and they are capable of differentiating into all the subsets of T cells,
as well as NK cells (32). At this stage, their cell-surface phenotype is c-kit+, Thy-1low,
CD44high, CD25-, and CD24low and their TCR genes are not yet rearranged.
The next stage of development is called DN2 or TN2 (33). In this stage, the cell
population expands rapidly, and TCR gene rearrangement also begins with
rearrangement of the TCR, TCR, and TCR loci, but the TCR locus remains
inaccessible to rearrangement. From this point, development of T cells branches into
and T cells, depending on the rearrangements that have occurred. T-cell
development proceeds with little additional proliferation and downregulation of CD25
and CD24 surface markers. In contrast, the T cells that have rearranged TCR begin a
complex pathway called selection. In the DN3 stage, the cells are fully committed to
the T-cell lineage (34). They stop proliferating, and TCR, , and gene
rearrangement proceeds very efficiently.
Figure 43.1. T-lymphocyte development and effector function. Stem cells from the bone
marrow travel to the thymus and develop into either CD4 or CD8 receptor positive T
lymphocytes. In the periphery, the CD4 T lymphocytes are activated by antigen-
presenting cells (B cells, macrophages, and dendritic cells) and differentiate into either a
T-helper (Th)-1 or Th-2 phenotype defined by their cytokine profiles. Th-2 CD4 T-
lymphocytes produce primarily IL-4, IL-6, and IL-10 cytokines, which stimulate B
lymphocytes to produce immunoglobulins (Ig), which are important in eliminating
extracellular organisms such as bacteria. If the T lymphocytes are inappropriately
activated, autoantibodies could be produced, leading to the development of
autoimmunity. Alternatively, Th-2 CD4 T lymphocytes produce primarily IL-2 and
interferon- (IFN-), which propagate cytotoxicity or cell-mediated immunity.
Cytotoxicity is important in destroying cancer cells and cells infected with intracellular
organisms such as viruses. The CD8 T lymphocyte produces primarily IL-2, IFN-, and
tumor necrosis factor- (TNF-), which enhances cytotoxic responses. The
macrophage plays an important role in various aspects of the immune response by
processing and presenting antigen to T lymphocytes. This diagram is not inclusive of all
aspects of the immune response, but it focuses on the elements discussed in this review.
The cell lineages then progress through DN4 and immature single-positive (ISP) cells to
the double-positive (DP) cells expressing CD8+CD4+CD3low (35). TCR, , and
rearrangement is stopped and TCR rearrangement is begun, CD25 is downregulated,
and CD4 and CD8 become expressed. Those DP cells that do not rearrange TCR to
allow interaction with major histocompatibility complex (MHC) molecules will die
within about 3 days. Only about 5% of DP cells meet these criteria, and about 30% of
this population in the spleen dies each day.
DP T cells that survive the selection process then branch once more into two lineages.
Those with TCRs that recognize MHC class II molecules tend to develop as CD4+
helper/regulatory T cells, whereas those with TCRs that recognize MHC class I
molecules develop into CD8+ cytotoxic T cells. After commitment to the CD8 or CD4
SP lineages, T cells continue to mature and eventually leave the thymus
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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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signaling is essential for the survival of B cells in the periphery (55).


On antigen binding to BCR, the complexes associate rapidly into cholesterol-rich lipid
rafts in the cell's plasma membrane (56). These lipid rafts also contain high
concentrations of the activating kinase Lyn, a member of the Src family kinase (SFK).
Early activation events initiate a cascade of kinase recruitment and activation through
transphosphorylation and cross-phosphorylation that culminates in binding of adaptor
proteins such as the B-cell linker protein (BLNK) and the B-cell cytoplasmic adaptor
protein (BCAP) (57). Although these proteins have no known intrinsic enzymatic
activity, they possess binding domains that allow assembly of the calcium initiation
complex (58,59). Sustained high levels of cytoplasmic calcium result in the activation
of nuclear factors NF-ATc and NF-B. The protein kinase C (PKC) enzyme pathway
(60), the phosphoinositol (PI)-3K/Akt pathway (also called protein kinase B, PKB,
pathway) (54), and the Ras/mitogen-activated protein kinase (Ras/MAPK) pathways are
also activated (61). These pathways regulate gene expression, cell survival, and cell
proliferation. They are complex, multistep pathways with numerous control points, and
their relative contributions depend on the stimulus applied.
Modulators of B-Cell Receptor Signaling
Several cell-surface proteins regulate the BCR signaling complex. Specifically, CD19
and CD22 both associate with the sIgM and may affect both the basal survival of the B
cell and the activation signals received through the BCR (62). CD19 enhances the B-
cell response, and CD22 acts as a negative regulator of the response. Coligation of the
BCR and CD19 with C3d-coupled antigen results in an approximately 1000-fold
decrease in the amount of antigen required for threshold activation of the B cell (63).
CD19 is phosphorylated by the SFK Lyn, which is transphosphorylated and activated as
well. When CD19 is coligated with the BCR, it acts as a transmembrane adaptor protein
and recruits PI-3K and Btk, thus upregulating the subsequent calcium response. The
Lyn that is activated by CD19 phosphorylates CD22, causing it to bind SHP-1 at its
immunomodulatory tyrosine-based inhibitory motif (ITIM) (64). It is postulated that
CD22 may target the ITAMs of Ig/Ig, Lyn, Syk, CD19, and PLC. Thus, CD22 is
activated through CD19 activation and serves to temper the CD19-mediated
enhancement of the BCR response.
FcRIIb is the Fc receptor for IgG on B cells (64). It is a glycoprotein with a ligand
binding extracellular domain and a cytoplasmic ITIM motif, and it binds with low
affinity to IgG. When the FcRIIb is coligated with the BCR, the tyrosine in the ITIM
is phosphorylated, creating an SH2 recognition site that recruits SH2-
domaincontaining inositol S-phosphatase (SHIP) (65). SHIP then hydrolyzes
PI(3,4,5) P3 to PI(3,4)P2, thus interfering with the binding of molecules such as Btk and
phospholipase C (PLC), which are involved in calcium responsiveness. Coligation of
FcRIIb also decreases phosphorylation of CD19 and recruitment of PI-3K to the
membrane. Because formation of IgG complexes is a feature of the late primary or
memory B-cell response, it is unlikely that FcRIIb affects initial activation of naive B
cells. It most likely serves to maintain peripheral B-cell tolerance and control ongoing
immunity and self-reactivity.
T-HelperMediated B-Cell Response
Although B cells can respond to some antigens independent of T-cell stimulation, they
respond to T-cell stimulation to produce affinity-matured immunity when they respond
to most protein antigens. On the initial encounter with foreign protein antigens, the DCs
of the innate immune system are activated. They migrate to the T-cell zones of the
draining lymph nodes and act as antigen-presenting cells (APCs). There they attract
naive T cells using CCR7 and CCR4 ligands and screen for TCRs with the
appropriate pMHC specificity (66). Activated effector Th cells then expand clonally
(67) and migrate to the T/B borders of secondary lymphoid organs to participate in the
regulation of B-cell development (68). Antigen-specific naive B cells recruited in the
early stages of inflammation relocate to the T/B border, and this increases the likelihood
of their contact with cognate Th cells (69). The B cells that recognize antigen and
internalize it then process and present this antigen on their surface as peptide/MHC
(70), functioning as APCs to acquire T-cell help. B cells are then stimulated to
differentiate into short-lived plasma cells (71), which produce large amounts of
antibody, and long-lived memory B cells (72), which are available for rapid response in
future encounters with the antigen. As discussed later, both nutrient deficiencies and
age-related changes have the potential to alter B-cell functions and, in particular, T-cell
functions.
T-Cell Signaling and Activation
The activation of naive T cells is a very complex and involved process that has recently
been described in detail (73). This complexity serves to enhance the specificity of the
response and maintain tolerance to self-antigens. TCR stimulation is a necessary but not
sufficient condition for T-cell activation. The action of costimulatory molecules is
required, and many interacting receptors and modulators can either enhance or inhibit
T-cell activation. The TCR consists of / or / heterodimers associated with up to
six other invariant proteins coded by four genes. The exact number of chains is not
known with certainty (74). Among these other proteins are / and / noncovalently
linked heterodimers of the CD3 complex and either a disulfide-linked homodimer of the
chain or a disulfide-linked heterodimer of the chain and the chain of the high-
affinity IgE Fc receptor (75). The / heterodimer is largely
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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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biologic function of antigen-stimulated (activation-induced) apoptosis seems to be to


promote tolerance to self and thereby avoid the development of autoimmunity.
As active cell death prevents overreaction during an immune response, passive cell
death or lymphokine withdrawal eliminates excess activated T cells after a successful
immune response is completed. This is similar to the death by neglect that occurs during
T-cell development. When the signal for activated T lymphocytes, typically IL-2, is
turned off as a result of reduced antigen stimulation, the T cells undergo apoptosis (96).
The exact steps involved are unknown at the present time (97).
Some activated T cells from an immune response persist without continued antigen
exposure as memory cells. These cells are thought to escape apoptosis by some means
(98). Another hypothesis is that these memory T cells do not escape apoptosis but are
continually replaced by an antigen dependent low-level proliferation of CD8+ T cells
that is probably maintained by IL-15 (99). Thus, a balance of a reduced rate of death
and proliferation results in a constant fraction of memory T cells over time.
B cells and DCs are also regulated by apoptosis. Apoptosis in B cells is similar in many
respects to that in T cells. B cells undergo a series of expansions and apoptotic
contractions in the bone marrow during their development (100). B cells undergo
selection in which nonproductive rearrangements of the Ig genes and B cells that
express BCRs directed at self-antigens are eliminated by apoptosis (101). In mature B
cells, receptors of the TNFR family such as Fas and CD40 regulate the balance of cell
survival and cell death (102). B-cell activation requires not only BCR ligation but also
ligation with CD40L, expressed on activated T cells, to prevent B-cell apoptosis (103).
Although DCs are known to undergo natural turnover in the mouse (104), the
mechanisms are not yet well defined.
ROLE OF NUTRIENTS IN INNATE AND ADAPTIVE IMMUNITY
In general, deficiency in any nutrient will result in the impairment of most adaptive and
innate immune responses. Furthermore, replenishing nutrient levels to normal
physiologic levels will, for the most part, restore appropriate immune function. A key
issue in today's society, in which nutrient supplementation is extremely popular, is what
effects specific nutrients have on various aspects of adaptive and innate immunity, when
these nutrients are consumed in excess. The following discussion focuses primarily on
the current literature, examining single nutrient studies, because in multivitamin or
mineral supplementation designs it is difficult to attribute the immune outcome to a
specific nutrient. The majority of the current literature in nutritional immunology
examines nutrient impact on T-lymphocyte functions. This focus is primarily because
the T cell is a key immunoregulatory cell involved in controlling both the type and the
extent of an immune response. In addition, it is relatively easy to obtain significant
numbers of T cells from the spleens of rodents and the peripheral blood of humans. A
significant body of literature also addresses the impact of nutrients on
monocyte/macrophages, DCs, and NK cells. Of the many nutrients our bodies need
daily, vitamins E, A, and D, dietary fat, including n-3 (-3) fatty acids and conjugated
fatty acids, and minerals such as selenium and zinc have been most intensively studied.
Dietary (caloric) restriction has also received significant attention because of its potent
antiaging effect in many experimental models. A key concept is that consuming
nutrients in excess can often be as detrimental as not consuming enough. The following
discussion focuses on recent findings for a few key nutrients and indicates what is
currently known about their potential mechanisms of action in the immune system.
Whenever possible, recent key reviews will be cited for the reader wanting more in-
depth information.
Innate Immunity
Monocytes and Macrophages
Dietary Restriction.
In general, calorie restriction (food restriction) has been shown to prolong life span and
improve immune function in long-lived strains of mice and rats (105). Either calorie
restriction or provision of n-3 fatty acids has been shown to delay the onset of diseases
such as autoimmune disorders in short-lived autoimmune diseaseprone mice (106).
However, young mice fed a calorie-restricted diet were more susceptible to sepsis from
experimentally induced peritonitis. Interestingly, macrophage function was reduced in
healthy mice following peritonitis, whereas macrophage function was greatly increased
in well-fed mice and survival was prolonged (107). The latter outcome is supported by
additional evidence showing enhanced prostaglandin and proinflammatory cytokine
production in the activated peritoneal macrophages of young calorie-restricted mice
(108).
n-3 Fatty Acids.
The n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (see
Chapter 5) derived from fish oil are known to act as antiinflammatory agents (109). n-3
fatty acids inhibit the production of macrophage-derived IL-12 (110), nitric oxide (111),
tumor necrosis factor- (TNF-) (112), and IL-6 (113) in vitro and in vivo. Some of
these effects, such as decreased IL-6 production, may result from n-3 fatty
aciddependent changes in prostaglandin production (114). The suppressive effects of
fish oil on macrophage function may have additional health benefits including
decreasing the loss of bone mass by inhibiting osteoclasts (bone macrophage-like cells)
and delaying heart disease by altering the lipid composition of arterial plaques (115) and
cholesterol flux in a macrophage-like monocytic cell line (116).
Conjugated Fatty Acids.
Conjugated linoleic acid (CLA) has been shown to be beneficial in preventing cachexia
in lipopolysaccharide-injected mice, which was
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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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autoimmune diseases such as such as some forms of diabetes (150). A more


comprehensive examination of the effects of vitamin D on DC gene expression was
conducted by Griffin and colleagues using gene microarray profiling (151).
Vitamin E.
Supplementation of tumor-bearing mice with -tocopherol succinate, an esterified
derivation of vitamin E, increased the immunotherapeutic effects of DC-dependent
slowing of tumor growth (152).
Adaptive Immunity
T and B Cells
The majority of the literature in nutrition immunology has focused on T cells more than
B cells. However, in many animal models, Ig levels, a reflection of B- and T-cell
function, have been measured in response to different dietary regimens. Whether these
effects represent a direct effect of diet on B-cell function or are indirect through
modulating T-cell function is not clear, and therefore the impact of diet on T-cell and B-
cell function is considered together. Very few studies have examined the impact of diet
on B-cell function directly.
Dietary Restriction.
Many data show that dietary restriction delays the onset of autoimmune diseases and
aging, in part by preventing disease and age-associated changes in T-cell function
(153,154). Dietary restriction is known to decrease proinflammatory cytokine,
chemokine, and adhesion molecule expression on T lymphocytes and gene expression
in transgenic mice (153, 155,156,157).
n-3 Fatty Acids.
n-3 fatty acids are well-known and widely studied dietary components because of their
antiinflammatory effects (109,158,159). Several reviews have described the effects of n-
3 fatty acids in humans (160) and in animal models (161) and have discussed their
potential mechanism of action (162). Of the n-3 fatty acids, EPA and DHA derived
from fish oil have received the most attention because they are considered to be the
most potent at delaying the onset of autoimmune disease in rodents (163). n-3 fatty
acids have also prevented bone loss in ovariectomized mice, in which they decrease
proinflammatory cytokines (164). Although the antiinflammatory effects of n-3 fatty
acids are beneficial, consuming an excess of n-3 fatty acids may be detrimental and may
possibly exacerbate certain types of infectious diseases. For example, mice fed a high
intake of n-3 fatty acids were rendered more susceptible to Listeria monocytogenes
infection (165).
In general, n-3 fatty acids are thought to exert their effects by reducing T-cell IL-2
production and subsequent cell proliferation. This effect has been shown fairly
consistently in rodents (158,166), humans ranging from young adults to the elderly
(160,167), and in vitro (168). Evidence from human feeding trials showed that the
antiinflammatory effects of dietary fish oil using purified n-3 fatty acids (EPA and
DHA) on T-cell function were negligible when humans consumed less than 2 g/day
(169). Another variable that affects the potency of n-3 fatty acids is the amount of n-3
fatty acid that is incorporated into T-cell membranes (170), which is also dependent on
the intake of competing fatty acids in other dietary fats. Although both EPA and DHA
can reduce T-cell proliferation, the cytokines and genes they regulate may be different,
as has been shown in vitro (171,172,173).
Some studies have begun to examine which T-cell subset is most affected by dietary
fish oil. Dietary fish oil inhibited antigen-driven murine CD4 T-cell proliferation both in
vitro (174) and in vivo (175). Dietary n-3 fatty acids may also inhibit the proliferation
of murine CD8 T cells, in addition to CD4 T cells, but the relative impact of n-3 fatty
acids appears to be dependent on the type of stimuli used (176) and on whether
costimulatory accessory cells are present (177). The mechanism by which dietary fish
oil inhibits the proliferation of CD4 T cells in this murine model appears to be by
inducing apoptosis in CD4 T cells expressing the Th-1 phenotype (178). Similar results
have been shown in vitro in the Jurkat human T-cell line (179). Increased apoptosis may
result from alterations in lipid raft formation and subsequent CD28 receptor function
(180). Currently, two consistent mechanisms have been proposed by which fish
oilderived n-3 fatty acids such as DHA may function. The first, as mentioned earlier,
is by changing the membrane lipid microenvironment and formation of lipid rafts, as
observed both in vitro and in vivo (181), which, in turn, may recruit appropriate
signaling molecules into close proximity. Another mechanism, which also may be a
result of altered lipid raft formation, is a reduction in the activity of the MAPKinase
signaling pathway, as shown in vitro (182).
Conjugated Fatty Acids.
CLA has been shown to have effects similar to those of n-3 fatty acids on cytokine
production. However, CLA appears to increase T-cell proliferation in mice (183). In
humans, CLA has been shown to improve the production of protective antibodies
against hepatitis B without any significant change in cytokine production (141).
Although these studies have yielded slightly different results depending on the model
used, the commonality is that dietary CLA inhibited immune-mediated disease in mice
(183) and decreased viral infectivity in pigs (184). However, CLA does not seem to
help replenish the immune system once an animal has become immunodepleted (185).
Treatment with CLA also resulted in a reduced number of B cells, whereas it enhanced
IgA and IgM antibody production (186). Which specific isomers of CLA are the most
immunopotent is not yet clear.
Vitamin A.
Retinoic acid has been shown to decrease the severity of autoimmune disease in mice
(187). Susceptibility to infection may be related to the association of vitamin A
deficiency with an increased production of IL-10, which favored the Th-2 phenotype
and decreased Th-1 responses in mice (188). The IL-10 producing Th-2 regulatory cells
then may downregulate not only Th-1
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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:
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Hughes DA, Bendich A, Darlington LG, eds. Diet and Human Immune Function.
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Paul WE, ed. Fundamental Immunology. 5th ed. Philadelphia: Lippincott Williams &
Wilkins, 2003.

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