Porth's Essentials of Pathophysiology, 4e

339

Innate and Adaptive Immunity

C h a p t e r 1 5

which activates macrophages and stimulates B cells to produce IgG antibodies that activate complement and coat pathogens for phagocytosis. T H 2 cells produce IL-4, which stimulates B cells to differentiate into IgE- secreting plasma cells; IL-5, which activates eosinophils; and IL-13, which activates mucosal epithelial cells to secrete mucus and expel microbes. Differentiated CD4 + T cells of the T H 1 subset recognize microbial peptides on macrophages and have the dual function of stimulating the production of IgG antibodies and eliminating cells infected with certain pathogenic intracellular microbes such as mycobacteria; whereas those of the T H 2 subset tend to recognize protein antigens or chemicals that stimulate the production of IgE and development of allergies. Activated T H 17 produces the cytokine IL-17, which promotes inflammation, and plays a role in the adaptive immune response and in some T cell–mediated inflammatory disorders. In most immune responses, a balanced response of T H 1 and T H 2 cells occurs, but immunization or exposure to antigen can skew the response to one or the other sub- set. For example, the extensive exposure to an allergen in atopic individuals has been shown to shift the naive CD4 + T cell toward a T H 2 response, with the production of the cytokines that influence IgE production and mast cell priming. An appreciation of these processes has led to clinical research that suggests that redirection of an allergic T H 2 response to a nonallergic T H 1 response can occur in atopic individuals through modified immuniza- tion protocols. CytotoxicT Cells Activated CD8 + lymphocytes become cytotoxic T cells after recognition of class I MHC–antigen complexes on target cell surfaces, such as body cells infected by viruses or transformed by cancer (Fig. 15-13). The recognition of 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 cells perform their killing function by injecting preformed cytotoxic proteins into target cells, thereby triggering apoptosis or programmed cell death (see Chapter 2). Cytotoxic T cells also produce and release cytokines, such as IFN- γ , which inhibits viral replication and is an important inducer of MHC class 1 molecule expression and macrophage activation. The CD8 + cytotoxic T cells are especially important in controlling replicating viruses and intracellular bacteria because antibodies cannot readily penetrate the mem- A recently defined type of T lymphocyte is the regula- tory T cell, which has CD4 and CD25 expressed on its cell membrane. Regulatory T cells, in contrast to CD4 + helper T cells, suppress immune responses by inhibiting the proliferation of other potentially harm- ful self-reactive lymphocytes. The actions of regulatory T cells are antigen specific. Activation of a regulatory brane of living cells. RegulatoryT Cells

TCR (already triggered)

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

T-cell receptor by the antigen prompts the secretion of the cytokine 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 that regulatory CD8 + T cells can selectively down-regulate T cells that are activated by either self or foreign antigens. These cells are thought to differentiate into effector cells during the primary immune response and function as suppressor cells dur- ing the secondary or memory phases of immunity, and are primarily involved in self–nonself discrimination. The potential clinical importance of regulatory T cells is suggested from animal studies showing inhibition of inflammatory bowel disease, experimental allergic encephalitis, and autoimmune diabetes by increased activity of regulatory T cells. Cell-Mediated Immunity Cell-mediated immunity functions against microbes, including bacteria, parasites, and all viruses that rep- licate inside cells where they cannot be destroyed by antibodies. Both CD8 + and CD4 + cells contribute to the response, with each having different effector mecha- nisms for the eradication of the infection. The effector functions of CD8 + cytotoxic T cells, which act against cells infected with viruses, are the most direct. Antigens derived from the virus multiply inside FIGURE 15-13. Destruction of target cell by cytotoxicT cell. Cytokines released from the activated helperT cell enhance the potential of the cytotoxicT cell in destruction of the target cell. IL, interleukin; MHC, major histocompatibility class;TCR,T-cell receptor.