Porth's Pathophysiology, 9e

Chapter 13 Innate and Adaptive Immunity    299

Regulatory T Cells Regulatory T cells (T R

TCR (already triggered)

) are a subset of T lymphocytes that function to control immune system responses. Different popu- lations of T R 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 “neg- ative regulators” of the immune process 34 . They suppress immune responses by inhibiting the proliferation of other potentially harmful self-reactive lymphocytes. Production of regulatoryTcells is highlydependent upon thepresenceof anti- gen, activation of a TCR by the antigen, and the release of the cytokines IL-10 and transforming growth factor- β (TGF- β ). 34 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 selec- tively 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 inflam- matory 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 pro- ductions from inside cells infected by viruses or transformed by cancer 33 (Fig. 13.11). The ability of CD8 + cells to recog- nize 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 pore-forming molecules ( i.e., perforins) or by triggering membrane molecules and intracellular apoptosis. Apoptosis is a normal biological process that eliminates excessive, danger- ous, 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., che- mokines) stimulate migration of several types of inflamma- tory cells, including macrophages, neutrophils, and ­basophils,

Activated helper T cell

CD4

IL-2

Cytokines

IL-2 receptor

Antigen

MHC-I

Cytotoxic T cell

Target cell (cell death)

CD8

TCR

Perforins Toxic cytokines

FIGURE 13.11  •  Destruction of target cell by cytotoxic T cell. ­Cytokines released from the activated helper T cell enhance the potential of the cytotoxic T cell in destruction of the target cell.

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, espe- cially IFN- γ . 23 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.