Effector Mechanisms of T Cell–Mediated Immunity - Clinicalkey
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Effector Mechanisms of T Cell–Mediated Immunity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... BOOK CHAPTER Effector Mechanisms of T Cell–Mediated Immunity Abul K. Abbas MBBS, Andrew H. Lichtman MD, PhD and Shiv Pillai MBBS, PhD Basic Immunology: Functions and Disorders of the Immune System, Chapter 6, 129-146 Host defense in which T lymphocytes serve as effector cells is called cell-mediated immunity. T cells are essential for eliminating microbes that survive and replicate inside cells and for eradicating infections by some extracellular microbes, often by recruiting other cells to clear the infectious pathogens. Cell-mediated immune responses begin with the activation of naive T cells to proliferate and to differentiate into effector cells. These effector T cells then migrate to sites of infection, and function to eliminate the microbes. In Chapter 3 we described the function of major histocompatibility complex (MHC) molecules in displaying the antigens of intracellular microbes for recognition by T lymphocytes, and in Chapter 5 we discussed the early events in the activation of naive T lymphocytes. In this chapter, we address the following questions: • What types of effector T cells are involved in the elimination of microbes? • How do effector T cells develop from naive T cells, and how do effector cells eradicate infections by diverse microbes? • What are the roles of macrophages and other leukocytes in the destruction of infectious pathogens? Types of T Cell–Mediated Immune Reactions Two main types of cell-mediated immune reactions eliminate different types of microbes: CD4 + helper T cells secrete cytokines that recruit and activate other leukocytes to phagocytose (ingest) and destroy microbes, and CD8 + cytotoxic T lymphocytes (CTLs) kill any infected cell containing microbial proteins in the cytosol, eliminating cellular reservoirs of infection ( Fig. 6-1 (f0010) ). Microbial infections may occur anywhere in the body, and some infectious pathogens are able to infect and live within host cells. 1 of 22 9/14/16, 2:24 PM Effector Mechanisms of T Cell–Mediated Immunity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... Pathogenic microbes that infect and survive inside host cells include (1) many bacteria, fungi, and protozoa that are ingested by phagocytes but resist the killing mechanisms of these phagocytes and thus survive in vesicles or cytosol, and (2) viruses that infect phagocytic and nonphagocytic cells and replicate in the cytosol of these cells (see Chapter 5, Fig. 5-1 ). The different classes of T cells recognize microbes in different cellular compartments and differ in the nature of the reactions they elicit. In general, CD4 + T cells recognize antigens of microbes in phagocytic vesicles and secrete cytokines that recruit and activate leukocytes that kill the microbes, whereas CD8 + cells recognize antigens of microbes that are present in the cytosol and destroy the infected cells. FIGURE 6-1 Cell-mediated immunity. A, Effector T cells of the CD4 + Th1 and Th17 subsets recognize microbial antigens and secrete cytokines that recruit leukocytes (inflammation) and activate phagocytes to kill the microbes. Effector cells of the Th2 subset (not shown) function in the eradication of infections by helminthic parasites. B, CD8 + cytotoxic T lymphocytes (CTLs) kill infected cells with microbes in the cytoplasm. CD8 + T cells also produce cytokines that induce inflammation and activate macrophages (not shown). Cell-mediated immunity against pathogens was discovered as a form of immunity to an intracellular bacterial infection that could be transferred from immune animals to naive animals by cells (now known to be T lymphocytes) but not by serum antibodies ( Fig. 6-2 (f0015) ). It was known from the earliest studies that the specificity of cell-mediated immunity against different microbes was a function of the lymphocytes, but the elimination of the microbes was a function of activated macrophages. As already mentioned, CD4 + T cells are mainly responsible for this classical type of cell-mediated immunity, whereas CD8 + T cells can eradicate infections without a requirement for phagocytes. 2 of 22 9/14/16, 2:24 PM Effector Mechanisms of T Cell–Mediated Immunity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... FIGURE 6-2 Cell-mediated immunity to an intracellular bacterium, Listeria monocytogenes. In these experiments, a sample of lymphocytes or serum (a source of antibodies) was taken from a mouse that had previously been exposed to a sublethal dose of Listeria organisms (immune mouse) and transferred to a normal (naive) mouse, and the recipient of the adoptive transfer was challenged with the bacteria. The number of bacteria were measured in the spleen of the recipient mouse to determine if the transfer had conferred immunity. Protection against bacterial challenge (seen by reduced recovery of live bacteria) was induced by the transfer of immune lymphoid cells, now known to be T cells (A) , but not by the transfer of serum (B) . The bacteria were killed in vitro by activated macrophages but not by T cells (C) . Therefore, protection depends on antigen-specific T lymphocytes, but bacterial killing is the function of activated macrophages. 3 of 22 9/14/16, 2:24 PM Effector Mechanisms of T Cell–Mediated Immunity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... T cell–mediated immune reactions consist of multiple steps (see Chapter 5, Fig. 5-2 ). Naive T cells are stimulated by microbial antigens in peripheral (secondary) lymphoid organs, giving rise to effector T cells whose function is to eradicate intracellular microbes. The differentiated effector T cells then migrate to the site of infection. Phagocytes at these sites that have ingested the microbes into intracellular vesicles display peptide fragments of microbial proteins bound to cell surface class II MHC molecules for recognition by CD4 + effector T cells. Peptide antigens derived from microbial proteins in the cytosol of infected cells are displayed by class I MHC molecules for recognition by CD8 + effector T cells. Antigen recognition activates the effector T cells to perform their task of eliminating the infectious pathogens. Thus, in cell-mediated immunity, T cells recognize protein antigens at two stages. First, naive T cells recognize antigens in lymphoid tissues and respond by proliferating and by differentiating into effector cells (see Chapter 5 ). Second, effector T cells recognize the same antigens anywhere in the body and respond by eliminating these microbes. This chapter describes how CD4 + and CD8 + effector T cells develop in response to microbes and eliminate these microbes. Because CD4 + helper T lymphocytes and CD8 + CTLs employ distinct mechanisms to combat infections, we discuss the development and functions of the effector cells of these lymphocyte classes individually. We conclude by describing how the two classes of lymphocytes may cooperate to eliminate intracellular microbes. Development and Functions of CD4 + Effector T Lymphocytes In Chapter 5 , we introduced the concept that effector cells of the CD4 + lineage could be distinguished on the basis of the cytokines they produce. These subsets of CD4 + T cells differ in their functions and serve distinct roles in cell-mediated immunity. Subsets of CD4 + Helper T Cells Distinguished by Cytokine Profiles Analysis of cytokine production by helper T (Th) cells has revealed that functionally distinct subsets of CD4 + T cells exist that produce different cytokines. The existence of these subsets explains how the immune system responds differently to different microbes. For example, intracellular microbes such as mycobacteria are ingested by phagocytes but resist intracellular killing. The adaptive immune response to such microbes results in the activation of the phagocytes to kill the ingested microbes. In contrast, the immune response to helminths is dominated by the production of immunoglobulin E (IgE) antibodies and the activation of eosinophils, which destroy the helminths. Both of these types of immune responses depend on CD4 + helper T cells, but for many years it was not clear how the CD4 + helper cells are able to stimulate such distinct immune effector mechanisms. We now know that these responses are mediated by subpopulations of CD4 + effector T cells that produce different cytokines. CD4 + helper T cells may differentiate into three major subsets of effector cells that produce distinct sets of cytokines that perform different functions in host defense ( Fig. 6-3 (f0020) ). (A fourth subset, follicular helper T cells, which is important in humoral immune responses, is discussed in Chapter 7 .) The subsets that were defined first are called Th1 cells and Th2 cells (for type 1 helper T cells and type 2 helper T cells); a third population, which was identified later, is called Th17 cells because its signature cytokine is interleukin(IL)-17. The discovery of these subpopulations has been an important milestone in understanding immune responses and provides 4 of 22 9/14/16, 2:24 PM Effector Mechanisms of T Cell–Mediated Immunity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... models for studying the process of cell differentiation. However, it should be noted that many activated CD4 + T cells may produce various mixtures of cytokines and therefore cannot be readily classified into these subsets, and there may be considerable plasticity