CELLS AND TISSUES OF THE IMMUNE SYSTEM
The cells of the immune system consist of lymphocytes, which are the mediators of
adaptive immunity; specialized antigen-presenting cells (APCs), which capture and
display microbial and other antigens to the lymphocytes; and various effector cells,
which perform the task of eliminating the antigens (typically, microbes), the ultimate
"effect" of the immune response. A remarkable feature of the immune system is how
intricately and efficiently the responses of these different cell types are orchestrated
and regulated.
Lymphocytes :
Lymphocytes are present in the circulation and in various lymphoid organs. Although
all lymphocytes appear morphologically identical, there are actually several
functionally and phenotypically distinct lymphocyte populations. Lymphocytes
develop from precursors in the generative lymphoid organs; T lymphocytes are so
called because they mature in the thymus, whereas B lymphocytes mature in the bone
marrow. Each T or B lymphocyte expresses receptors for a single antigen, and the
total population of lymphocytes (numbering about 1012 in humans) is capable of
recognizing tens or hundreds of millions of antigens. This enormous diversity of
antigen recognition is generated by the somatic rearrangement of antigen receptor
genes during lymphocyte maturation, and variations that are introduced during the
joining of different gene segments to form antigen receptors. These antigen receptors
are rearranged and expressed in lymphocytes but not in any other cell. Therefore, the
demonstration of antigen receptor gene rearrangements by molecular methods (e.g.,
polymerase chain reaction, or PCR) is a definitive marker of T or B lymphocytes.
Such analyses are used in classification of lymphoid malignancies . Furthermore,
because each lymphocyte has a unique DNA rearrangement (and hence a unique
antigen receptor), molecular analysis of the rearrangement in a cell population can be
used to distinguish polyclonal (non-neoplastic) lymphocyte proliferations from
monoclonal (neoplastic) expansions.
T Lymphocytes :
Thymus-derived, or T, lymphocytes are the effector cells of cellular immunity and
provide important stimuli for antibody responses to protein antigens. T cells constitute
60% to 70% of the lymphocytes in peripheral blood and are the major lymphocyte
population in splenic periarteriolar sheaths and lymph node interfollicular zones. T
cells do not detect free or circulating antigens. Instead, the vast majority (>95%) of T
cells recognize only peptide fragments of protein antigens that are displayed on other
cells bound to proteins of the major histocompatibility complex (MHC; or in humans,
human leukocyte antigen [HLA] complex). The MHC was discovered on the basis of
studies of graft rejection or acceptance (tissue, or "histo," compatibility). It is now
known that the normal function of MHC molecules is to display peptides for
recognition by T lymphocytes. By forcing T cells to see MHC-bound peptides, the
system ensures that T cells can recognize antigens in other cells and thus perform
their function of killing infected cells or activating phagocytes or B lymphocytes that
have ingested protein antigens. In every individual, T cells recognize only peptides
displayed by that individual's MHC molecules, which, of course, are the only MHC
molecules that the T cells will encounter normally. This phenomenon is called MHC
restriction. In MHC-restricted T cells, the T-cell receptor (TCR) is a heterodimer
composed of disulfide-linked α and β protein chains (Fig. 5-3A); each chain has a
variable region that participates in binding a particular peptide antigen and a constant
region that interacts with associated signaling molecules. MHC molecules are
described below.
TCRs are noncovalently linked to a cluster of five invariant polypeptide chains, the γ,
δ, and ε proteins of the CD3 molecular complex and two ζ chains (see Fig. 5-3A). The
CD3 proteins and ζ chains do not themselves bind antigens; instead, they interact with
the constant region of the TCR to transduce intracellular signals after TCR
recognition of antigen. In addition to these signaling proteins, T cells express a
number of other invariant function-associated molecules. CD4 and CD8 are expressed
on distinct T-cell subsets and serve as coreceptors for T-cell activation. During
antigen recognition, CD4 molecules on T cells bind to invariant portions of class II
MHC molecules (see later) on selected APCs; in an analogous fashion, CD8 binds to
class I MHC molecules. CD4 is expressed on approximately 60% of mature T cells,
whereas CD8 is expressed on about 30% of T cells; in normal healthy individuals, the
CD4/CD8 ratio is about 2 : 1. The CD4- and CD8-expressing T cells (called CD4+
and CD8+ cells, respectively) perform different but overlapping functions. CD4+ T
cells are "helper" T cells because they secrete soluble molecules (cytokines) that help
B cells to produce antibodies (the origin of the name "helper" cells) and also help
macrophages to destroy phagocytosed microbes. The central role of CD4+ helper cells
in immunity is highlighted by the severe compromise that results from the destruction
of this subset by human immunodeficiency virus (HIV) infection. CD8+ T cells can
also secrete cytokines, but they play a more important role in directly killing virusinfected or tumor cells, and hence are called "cytotoxic" T lymphocytes (CTLs).
Other important invariant proteins on T cells include CD28, which functions as the
receptor for molecules that are induced on APCs by microbes (and are called
costimulators), and various adhesion molecules that strengthen the bond between the
T cells and APCs and control the migration of the T cells to different tissues.
In a minority of peripheral blood T cells and in many of the T cells associated with
mucosal surfaces (e.g., lung and gastrointestinal tract), the TCRs are heterodimers of γ
and δ chains, which are similar but not identical to the α and β chains of most TCRs.
Such γδ T cells do not express CD4 or CD8 and recognize nonprotein molecules (e.g.,
bacterial lipoglycans), but their functional roles are not well understood. Another
small population of T cells expresses markers of T cells and NK cells. These NKT
cells recognize microbial glycolipids, but their importance in host defense is also not
established. The antigen receptors of γδ T cells and NKT cells are much less diverse
than the receptors of "conventional" T cells, suggesting that the former recognize
conserved microbial structures. In this respect, γδ T cells and NKT cells resemble
cells of innate immunity.
Another population of T cells that is receiving great attention is called regulatory T
lymphocytes. This cell type is described later, in context of tolerance of self antigens.
MHC Molecules:
the Peptide Display System of Adaptive Immunity
Because MHC molecules are fundamental to T-cell recognition of antigens, and
variations in MHC molecules are associated with immunologic diseases, it is
important to review the structure and function of these molecules. The human MHC,
known as the human leukocyte antigen (HLA) complex, consists of a cluster of genes
on chromosome 6 . The HLA system is highly polymorphic; that is, there are several
alternative forms (alleles) of a gene at each locus (e.g., >400 different HLA-B alleles
have been described). Such diversity provides a system whereby a vast array of
peptides can be displayed by MHC molecules for recognition by T cells. As we shall
see, this polymorphism also constitutes a formidable barrier to organ transplantation.
On the basis of their chemical structure, tissue distribution, and function, MHC gene
products fall into three categories:
Class I MHC molecules are encoded by three closely linked loci, designated
HLA-A, HLA-B, and HLA-C . Each of these molecules is a heterodimer,
consisting of a polymorphic 44-kD α chain noncovalently associated with a
12-kD nonpolymorphic β2-microglobulin (encoded by a separate gene on
chromosome 15). The extracellular portion of the α chain contains a cleft
where foreign peptides bind to MHC molecules for presentation to CD8+ T
cells. In general, class I MHC molecules bind to peptides derived from
proteins synthesized within the cell (e.g., viral antigens). Because class I MHC
molecules are present on all nucleated cells, all virus-infected cells can be
detected and eliminated by CTLs.Class II MHC molecules are encoded by
genes in the HLA-D region, which contains at least three subregions: DP, DQ,
and DR. Class II MHC molecules are heterodimers of noncovalently linked
polymorphic α and β subunits (see Fig. 5-4). As in class I, the extracellular
portion of the class II MHC heterodimer contains a cleft for the binding of
antigenic peptides. Unlike in class I, the tissue distribution of class II MHCexpressing cells is quite restricted; they are constitutively expressed mainly on
APCs (notably, dendritic cells), and macrophages, and B cells. In general,
class II MHC molecules bind to peptides derived from proteins synthesized
outside the cell (e.g., those derived from extracellular bacteria). This allows
CD4+ T cells to recognize the presence of extracellular pathogens and to
orchestrate a protective response.Class III proteins include some of the
complement components (C2, C3, and Bf); genes encoding tumor necrosis
factor (TNF) and lymphotoxin (LT, or TNF-β) are also located within the
MHC. Although genetically linked to class I and II molecules, class III
molecules and the cytokine genes do not form a part of the peptide display
system and will not be discussed further.
Every individual inherits one HLA allele from each parent and thus typically
expresses two different molecules for every locus. Cells of a heterozygous individual
can therefore express six different class I HLA molecules: three of maternal origin
and three of paternal origin. Similarly, a given individual expresses maternal and
paternal alleles of the class II MHC loci; because some HLA-D α and β chains can
mix and match with each other, each class II-expressing cell can have as many as 20
different class II MHC molecules. Different MHC alleles bind to different peptide
fragments depending on the particular amino acid sequence of a given peptide; the
expression of many different MHC molecules allows each cell to present a wide array
of peptide antigens.
As a result of the polymorphism at the major HLA loci in the population, a virtually
infinite number of combinations of molecules exist, and each individual expresses a
unique MHC antigenic profile on his or her cells. The combination of HLA alleles in
each individual is called the HLA haplotype. The implications of HLA polymorphism
are obvious in the context of transplantation-because every individual has HLA alleles
that differ to some extent from every other individual, grafts from any person will
evoke immune responses in any other person and be rejected (except, of course, for
identical twins). In fact, HLA molecules were discovered in the course of early
attempts at tissue transplantation. HLA molecules of the graft evoke both humoral and
cell-mediated responses, eventually leading to graft destruction (discussed later in this
chapter). This ability of MHC molecules to trigger immune responses is the reason
these molecules are often called "antigens." It is believed that the polymorphism of
MHC genes arose to enable the population to display and respond to any conceivable
microbial peptide.
The role of the MHC in T-cell stimulation also has important implications for the
genetic control of immune responses. The ability of any given MHC allele to bind the
peptide antigens generated from a particular pathogen will determine whether an
individual's T cells can actually "see" and respond to that pathogen. In other words, an
individual will recognize and mount an immune response against a given antigen only
if he or she inherits MHC molecules that can bind the antigenic peptide and present it
to T cells. The inheritance of particular alleles influences both protective and harmful
immune responses. For example, if the antigen is ragweed pollen and the response is
an allergic reaction, inheritance of some HLA genes may make individuals
susceptible to this disease. On the other hand, good responsiveness to a viral antigen,
determined by inheritance of certain HLA alleles, may be beneficial for the host.
Finally, many diseases are associated with particular HLA alleles. These HLA-linked
diseases can be broadly grouped into the following categories: (1) inflammatory
diseases, including ankylosing spondylitis and several postinfectious arthropathies, all
associated with HLA-B27; and (2) autoimmune diseases, including autoimmune
endocrinopathies, associated with certain DR alleles. The mechanisms underlying all
these associations are not understood at present. The best known association is
between ankylosing spondylitis and the HLA-B27 allele; individuals who possess this
allele have a 90-fold greater chance (relative risk) of developing the disease than do
those who are negative for HLA-B27. We will return to a discussion of HLA linkage
when we consider autoimmune diseases.
B Lymphocytes
Bone marrow-derived, or B, lymphocytes comprise 10% to 20% of the circulating
peripheral lymphocyte population. They are also present in bone marrow and in the
follicles of peripheral lymphoid tissues (lymph nodes, spleen, tonsils, and other
mucosal tissues). Stimulation of follicular B cells leads to the formation of a central
zone of large, activated B cells in follicles, called a germinal center. B cells are the
only cell lineage that synthesize antibodies, also called immunoglobulins (Ig).
B cells recognize antigen via monomeric membrane-bound antibody of the
immunoglobulin M (IgM) class, associated with signaling molecules to form the Bcell receptor (BCR) complex . Whereas T cells can recognize only MHC-associated
peptides, B cells can recognize and respond to many more chemical structures,
including proteins, lipids, polysaccharides, nucleic acids, and small chemicals;
furthermore, B cells (and antibodies) recognize native (conformational) forms of these
antigens. As with TCRs, each antibody has a unique antigen specificity. The diversity
of antibodies is generated during somatic rearrangements of Ig genes. B cells express
several invariant molecules that are responsible for signal transduction and for
activation of the cells . These molecules include the CD40 receptor, which binds to its
ligand expressed on helper T cells, and CD21 (also known as the CR2 complement
receptor), which recognizes a complement breakdown product that is frequently
deposited on microbes.
After stimulation, B cells differentiate into plasma cells, which secrete large amounts
of antibodies, the mediators of humoral immunity. There are five classes, or isotypes,
of immunoglobulins: IgG, IgM, and IgA constitute more than 95% of circulating
antibodies. IgA is the major isotype in mucosal secretions, IgE is present in the
circulation at very low concentrations and is also found attached to the surfaces of
tissue mast cells, and IgD is expressed on the surfaces of B cells but is not secreted.
As outlined below, each isotype has characteristic abilities to activate complement or
recruit inflammatory cells and thus plays a different role in host defense and disease
states.
Natural Killer Cells
Natural killer (NK) cells are lymphocytes that arise from the common lymphoid
progenitor that gives rise to T and B lymphocytes. However, NK cells are cells of
innate immunity and do not express highly variable and clonally distributed receptors
for antigens. Therefore, they do not have specificities as diverse as do T cells or B
cells. NK cells use a limited set of activating receptors to recognize molecules
expressed on stressed or infected cells or cells with DNA damage, and then kill these
cells, thus eliminating irreparably damaged cells and potential reservoirs of infection.
NK cells have another unique specificity. To avoid attacking normal host cells, NK
cells express inhibitory receptors that recognize self class I MHC molecules, which
are expressed on all healthy cells; engagement of these inhibitory receptors typically
overrides the activating receptors and thus prevents activation of the NK cells.
Infections (especially viral infections) and stress are associated with loss of
expression of class I MHC molecules. When this happens, the NK cells are released
from their inhibition and are able to respond to the activating ligands that were
induced by the stress and ultimately destroy the unhealthy host cells.