298
UNIT IV
Infection, Inflammation, and Immunity
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 fac-
tor 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 des-
ignated 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 predomi-
nant 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 vari-
ous 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 pro-
cessed 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.
33
The majority of TCRs recognize anti-
genic 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 sur-
face molecules known as the
CD3 complex
, which also aid in
cell signaling.
Helper T Cells and Cytokines in
Adaptive Immunity
The activation of helper T cells is the central event in the ini-
tiation of the humoral and cell-mediated immune response.
CD4
+
helper T cells (T
H
) 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 spe-
cific 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 miss-
ing, 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 endo-
thelial cells, enabling transmigration of leukocytes, and by
stimulating antibody production.
23
Another cytokine essential
for CD4
+
function is IL-6. IL-6 influences T cell effector func-
tions by promoting helper T cell (T
2
H) differentiation through
up-regulation of NFATc2 and c-maf.
31
The activated CD4
+
helper T cell can differentiate into
two distinct subpopulations of helper T cells (
i.e.,
T
1
H or T
2
H)
based on the cytokines secreted by the APCs at the site of
activation (Table 13.5). Macrophages and DCs produce IL-12,
which directs the maturation of CD4
+
helper T cells toward
the T
1
H subtype, whereas mast cells and T cells produce IL-4,
which induces differentiation toward the T
2
H subtype. The
T
2
H cells direct B lymphocytes to switch class and produce
the IgE antibodies necessary for an allergic or hypersensitivity
response. The distinct pattern of cytokine secreted by mature
T
1
H and T
2
H cells further defines these subpopulations of
T
H
cells and determines whether a humoral or cell-mediated
response will ultimately occur. Activated T
1
H cells produce
the cytokines IL-2 and IFN-
γ
, whereas T
2
H cells produce IL-4
and IL-5. IL-5 is an activator of eosinophils that, along with
IgE, functions in the control of helminth (intestinal parasite)
infections. Some of the cytokines (
e.g.,
IL-10) made by T
2
H
cells are anti-inflammatory and inhibit macrophage activation
and suppress other T
1
H responses.
TABLE 13.5 COMPARISON OF PROPERTIES OF HELPER T-CELL SUBTYPES 1 (T
1
H) AND 2 (T
2
H)
T
1
H
T
2
H
Stimulus for differentiation to T
H
subtype
Microbes
Allergens and parasitic worms
Cells and cytokines influencing
T
H
subtype maturation
IL-12 produced by macrophages and DCs
IL-4 produced by mast cells and T cells
Cytokines secreted by T
H
subtype
IFN-
γ
, IL-2
IL-4, IL-5
Effector functions
Phagocyte-mediated defense against
infections, especially intracellular
microbes; stimulates production of IgG
IgE- and eosinophil/mast cell–mediated
immune reactions; stimulates production
of IgE
NK, natural killer; IL, interleukin; IFN, interferon; Ig, immunoglobulin.
