T Lymphocytes and
Cellular Immunity
T lymphocytes serve many functions in the
immune system including the
activation of other T cells and B cells, control of intracellular viral
infections, rejection of foreign tissue grafts, activation of autoimmune
processes, and activation of delayed hypersensitivity reactions. These
processes make up the body’s cell-mediated or cellular immunity.
The effector phase of cell-mediated immunity is carried out by T lymphocytes
and macrophages.
T
lymphocytes arise from lymphoid stem cells in the bone marrow, but unlike B
lymphocytes, they migrate to the thymus gland to undergo the process of
maturation. The thymus gland is richly innervated and produces several peptide hormones
such as thymulin
and thymopoietin, which
are believed to be
involved in T-cell maturation. T-cell precursors are attracted to the thymus by
thymotaxin, a chemotactic factor secreted by thymic epithelial cells. Once the
prothymocyte enters the cortex of the thymus, terminal deoxynucleotidyl
transferase (TdT) is expressed causing gene rearrangement and increased TCR
diversity. The pre–T lymphocytes are designated CD3+, CD4−,
CD8−, and double negative cells. The majority of these cells go on
to rearrange their alpha and beta chain gene segments. The beta segment is
expressed first resulting in the formation of a pre-TCR. This halts further
gene rearrangement, enhances alpha chain gene rearrangement, and causes full
maturation and expression of CD4+ (helper) and CD8+
(cytotoxic) lymphocytes. These are the predominant lymphocytes in the body.
Mature T lymphocytes leave the thymus and migrate to peripheral lymphoid
tissues, where they multiple and differentiate into memory T cells and various
other mature lymphocytes upon encountering an antigen.
The TCR
on the mature lymphocyte is composed of two polypeptides that fold to form a
groove that recognizes processed antigen peptide–MHC complexes. It consists of
two transmembrane molecules, the TCR-α and the TCR-β, that are the result of
rearrangement of first the TCR-β and then the TCR-α gene. The majority of TCRs
recognize antigenic peptides that are bound to MHC-derived molecules. The TCR
is associated with several surface molecules such as CD4 and CD8. CD4 is
associated with the helper T cell, and CD8 is associated with the cytotoxic T
cell. CD4 and CD8 help stabilize the TCR–antigen–MHC complex during T-cell
activation. The TCR is also associated with other surface molecules known as
the CD3 complex, which also aid in cell
signaling.
Helper
T Cells and Cytokines invAdaptive Immunity
The
activation of helper T cells is the central event in the initiation of the
humoral and cell-mediated immune response. CD4+ helper T cells (T ) serve as
master regulators for the immune system. They become activated when their TCRs
interact with antigens that are complexed with class II MHC on the surface of
APCs. Once CD4+ cells are
activated, the cytokines they
secreted in response influence the function of nearly
all other cells of the immune system. Depending upon the specific cytokine that
is released by the CD4+ T cell the subsequent immunologic response
will be activated. These cytokines are able to activate and regulate B cells,
cytotoxic T lymphocytes, NK cells, macrophages, and other immune cells. The
first cytokine to be produced by CD4+ T cells after activation is
IL-2. IL-2 is necessary for the proliferation and function of helper T cells,
cytotoxic T cells, B cells, and NK cells. IL-2 interacts with T lymphocytes by
binding to specific membrane receptors that are present on activated T cells
but not on resting T cells. T-cell amplification relies on the presence of both
IL-2 and IL-2 receptors; if either is missing, cell proliferation ceases. There
are other cytokines that are not produced by CD4+, but are essential
for its function. IL-1 is produced by inflammatory cells and is responsible for
increasing the expression of adhesion molecules on endothelial cells, enabling
transmigration of leukocytes, and by stimulating antibody production. Another
cytokine essential for CD4+ function is IL-6. IL-6 influences T cell effector functions
by promoting helper T cell (T H) differentiation through up-regulation of
NFATc2 and c-maf.
Regulatory
T Cells
Regulatory
T cells (TR) are a subset of T
lymphocytes that function to control immune system responses. Different
populations of TR cells produced in the thymus have been
identified including those that
express CD4 and CD25 on their surface. These cells represent a subset of CD4+
cells that act as “negative regulators” of the immune process34. They suppress
immune responses by inhibiting the proliferation of other potentially harmful
self-reactive lymphocytes. Production of regulatory T cells is highly dependent
upon the presence of antigen, activation of a TCR by the antigen, and the
release of the cytokines IL-10 and transforming growth factor-β (TGF-β). These
cytokines inhibit the proliferation and activation of lymphocytes and
macrophages. There is also recent evidence of the existence of regulatory CD8+
T cells that can selectively down-regulate T cells activated by either self or
foreign antigens. These cells differentiate into regulatory cells during the
primary immune response and function to suppress the secondary immune response.
The CD8+ regulators are, there-fore, primarily involved in
self–nonself discrimination. The ability of the regulatory T cells to control
many aspects of the immune response has significant implications for clinical
practice. Promise has been shown in the control of inflammatory bowel disease,
experimental allergic encephalitis, and autoimmune
diabetes.
Cytotoxic
T Cells
The
primary function of cytotoxic T (CD8+) cells is to monitor the
activity of all cells in the body and destroy any that threaten the integrity
of the body. CD8+ T cells recognize antigens that are presented on
the cell surface by MHC class I–derived molecules that sample peptides from
protein degradation productions from inside cells infected by viruses or transformed
by cancer (Fig. 13.11). The ability of CD8+ cells to recognize the
class I MHC–antigen complexes on infected target cells ensures that neighboring
uninfected host cells, which express class I MHC molecules alone or with
self-peptide, are not indiscriminately destroyed.
The CD8+ cytotoxic T lymphocytes destroy target cells
by a variety of mechanisms including the release of cytolytic enzymes, toxic
cytokines, and poreforming molecules (i.e., perforins) or by triggering
membrane molecules and intracellular apoptosis. Apoptosis is a normal
biological process that eliminates excessive, dangerous, or damaged cells from
the body. The CD8+ T cells play a large role in controlling replicating viruses
and intracellular bacteria because antibody cannot readily penetrate the mem-
brane of living cells.
Cell-Mediated
Immunity
In order
for the cell-mediated immune response to carry out its function, healthy CD4+
and CD8+ T lymphocytes are required. Activated CD4+
helper T cells release various cytokines (i.e., IFN-γ) that recruit and
activate other CD8+ cytotoxic T cells, macrophages, and inflammatory
cells. Cytokines (e.g., chemokines) stimulate migration of several types
of inflammatory cells, including macrophages, neutrophils, and basophils, which further
enhances the phagocytic,
metabolic, and enzymatic functions of the cell-mediated immune
response. This results in a more rapid and more efficient destruction of
infected cells. This type of defense is important against many intracellular
pathogens such as Mycobacterium species and Listeria monocytogenes but
unfortunately plays a role in delayed hypersensitivity reactions. Allergic
contact dermatitis (delayed hypersensitivity type IV) results from the
activation of both CD4+ and CD8+ T-cell precursors in the
lymph nodes draining the site of antigen presentation. These “haptenated
peptides” stimulate the recruitment of T cells at the site of anti- gen
presentation, inducing inflammatory signals and apoptosis of epidermal cells,
leading to the development of inflammation, to the release of chemical
mediators, and to clinical symptoms.
In
cell-mediated immune responses, the
actions of T lymphocytes and
effector macrophages predominate. The most aggressive and abundant phagocyte,
the macrophage, becomes activated after exposure to T-cell cytokines, especially
IFN-γ. The initial stages of cell-mediated immunity are initiated when an APC
displays an antigen peptide–class I or II MHC complex to the CD4+
helper T cell and activates it. The activated helper T cell then synthesizes
IL-2, IL-4, and other cytokines, which stimulate increased production of CD4+
helper T cells and then amplify the response. Additional cytokine release
enhances the activity of cytotoxic T cells and effector
macrophages.
