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.
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.