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UNIT IV Infection, Inflammation, and Immunity

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.

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

TABLE 13.5 COMPARISON OF PROPERTIES OF HELPER T-CELL SUBTYPES 1 (T 1

H) AND 2 (T 2

H)

T

H

T

H

1

2

Microbes

Allergens and parasitic worms

Stimulus for differentiation to T H subtype Cells and cytokines influencing T H subtype maturation Cytokines secreted by T H subtype

IL-12 produced by macrophages and DCs

IL-4 produced by mast cells and T cells

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.