Effector Mechanisms of T Cell–Mediated Immunity: Functions of T Cells in Host Defense

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 leukocytes to clear the infectious pathogens. T cells also destroy tumors that produce proteins that are recognized as foreign antigens (see Chapter 10 ). In this chapter, we focus on the role of T cell responses in defense against pathogenic microbes. Cell-mediated immune responses begin with the activation of naive T cells to proliferate and to differentiate into effector cells. The majority of these effector T cells then migrate to sites of infection, where they function to eliminate the microbes. Some CD4 + effector cells stay in lymphoid organs and help B lymphocytes to produce high-affinity antibodies (humoral immunity, see Chapter 7 ). 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 express molecules that recruit and activate other leukocytes to phagocytose (ingest) and destroy microbes, and CD8 + cytotoxic T lymphocytes (CTLs) kill infected cells containing microbial proteins in the cytosol, thus eliminating cellular reservoirs of infection ( Fig. 6.1 ). Microbial infections may occur anywhere in the body, and some infectious pathogens are able to infect and live within host cells. 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 in the cytosol, and (2) viruses that infect phagocytic and nonphagocytic cells and replicate in these cells (see Chapter 5 , Fig. 5.1 ). CD4 + and CD8 + 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 that may be intracellular or extracellular (based on where the microbes survive and replicate) but whose antigens are internalized into endocytic vesicles. These T cells secrete cytokines that recruit and activate phagocytes and other leukocytes that kill the microbes. In contrast, CD8 + T cells recognize microbial antigens that are present in the cytosol of infected cells and destroy these cells.

Fig. 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) recruit eosinophils, which destroy helminthic parasites. B, CD8 + cytotoxic T lymphocytes (CTLs) kill infected cells with microbial antigens in the cytosol. 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 ). It was known from early studies that lymphocytes were responsible for the specificity of cell-mediated immunity against different microbes, 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.

Fig. 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.

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 the infections. The differentiated effector T cells then migrate to the site of infection. Phagocytes at these sites that have ingested the microbes or microbial proteins into intracellular vesicles display peptide fragments of the protein antigens 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 use 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 and that eliminate different types of pathogens. The existence of these subsets illustrates how the immune system mounts specialized responses that are optimized to combat diverse 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, enabling them 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. The immune response to extracellular bacteria and fungi requires cytokines that help to drive neutrophilic inflammation, because neutrophils in large numbers are needed to eliminate these pathogens. All 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 subsets of effector cells that produce distinct sets of cytokines that function to defend against different types of microbial infections in tissues, and a fourth subset that activates B cells in secondary lymphoid organs ( Fig. 6.3 ). 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, respectively); the third population, which was identified later, is called Th17 cells because its signature cytokine is interleukin (IL)-17. The T cells that help B lymphocytes, called follicular helper T (Tfh) cells, are described in Chapter 7 and will not be considered further in this chapter. The discovery of these subpopulations has been an important milestone in understanding immune responses and provides models for studying the process of cell differentiation. However, it should be noted that some activated CD4 + T cells may produce mixtures of cytokines and therefore cannot be readily classified into these subsets, and there may be plasticity in these populations so that one subset may convert into another under some conditions. Despite these caveats, considering the functions of CD4 + effector cells in the context of the major subsets is helpful for understanding the mechanisms of cell-mediated immunity.

Fig. 6.3

Characteristics of subsets of CD4 + helper T lymphocytes.

A naive CD4 + T cell may differentiate into subsets that produce different cytokines that recruit and activate different cell types (referred to as target cells ) and combat different types of infections in host defense. These subsets also are involved in various kinds of inflammatory diseases. The table summarizes the major differences among Th1, Th2, Th17 , and Tfh subsets of helper T cells. IFN , Interferon; IL , interleukin.

The cytokines produced in adaptive immune responses include those made by the Th subsets, as well as cytokines produced by CD4 + regulatory T cells and CD8 + T cells. These cytokines of adaptive immunity share some general properties, but they each have different biologic activities and play unique roles in the effector phase or regulation of these responses ( Fig. 6.4 ). The functions of the CD4 + T cell subsets reflect the actions of the cytokines they produce. Similar sets of cytokines may be produced early in immune responses by innate lymphoid cells, such as ILC1, ILC2, and ILC3 (see Chapter 2 ), and later by Th1, Th2, and Th17 cells, respectively. These combined innate and adaptive responses with similar cytokine profiles and functional outcomes are sometimes grouped under “type 1 immunity,” “type 2 immunity,” and “type 3 immunity.”

Fig. 6.4

Properties of the major cytokines produced by CD4+ helper T lymphocytes.

A, General properties of cytokines produced during adaptive immune responses. B, Functions of cytokines involved in T cell–mediated immunity. Note that IL-2, which is produced by T cells early after activation and is the first identified T cell cytokine, was discussed in Chapter 5 in the context of T cell activation. Transforming growth factor β (TGF-β) functions mainly as an inhibitor of immune responses; its role is discussed in Chapter 9 . The cytokines of innate immunity are shown in Fig. 2.14 ; several of these are also made by T cells and thus function in adaptive immunity as well. More information about these cytokines and their receptors is provided in Appendix III. IgE, Immunoglobulin E; IL, interleukin.

Each subset of CD4 + T cells develops in response to the types of microbes that subset is best at eradicating. Different microbes elicit the production of different cytokines from dendritic cells and other cells, and these cytokines drive the differentiation of antigen-activated T cells to one or another subset. We next discuss the functions and development of each of the major subsets of CD4 + effector T cells.

Th1 Cells

The Th1 subset is induced by microbes that are ingested by and activate phagocytes, primarily macrophages, and Th1 cells stimulate phagocyte-mediated killing of ingested microbes ( Fig. 6.5 ). The signature cytokine of Th1 cells is interferon-γ (IFN-γ), the most potent macrophage-activating cytokine known. (Despite its similar name, IFN-γ is a much less potent antiviral cytokine than the type I IFNs [see Chapter 2 ]).

Fig. 6.5

Functions of Th1 cells.

Th1 cells produce the cytokine interferon-γ (IFN-γ) , which activates macrophages to kill phagocytosed microbes (classical pathway of macrophage activation). In mice, IFN-γ stimulates the production of IgG antibodies, but this has not been established in humans. APC, Antigen-presenting cell.

Th1 cells, acting through CD40 ligand and IFN- γ , increase the ability of macrophages to kill phagocytosed microbes ( Fig. 6.6 ). Macrophages ingest and attempt to destroy microbes as part of the innate immune response (see Chapter 2 ). The efficiency of this process is greatly enhanced by the interaction of Th1 cells with the macrophages. When microbes are ingested into phagosomes of the macrophages, microbial peptides are presented on class II MHC molecules and are recognized by CD4 + T cells. If these T cells belong to the Th1 subset, they are induced to express CD40 ligand (CD40L, or CD154) and to secrete IFN-γ. Binding of CD40L to CD40 on macrophages functions together with IFN-γ binding to its receptor on the same macrophages to trigger biochemical signaling pathways that lead to the generation of reactive oxygen species (ROS) and nitric oxide (NO) and activation of lysosomal proteases. All these molecules are potent destroyers of microbes. The net result of CD40-mediated and IFN-γ–mediated activation is that macrophages become strongly microbicidal and can destroy most ingested microbes. This pathway of macrophage activation by CD40L and IFN-γ is called classical macrophage activation , in contrast to Th2-mediated alternative macrophage activation, discussed later. Classically activated macrophages, often called M1 macrophages, also secrete cytokines that stimulate inflammation and express increased levels of MHC molecules and costimulators, which amplify the T cell response. CD8 + T cells secrete IFN-γ as well, and may contribute to macrophage activation and killing of ingested microbes.

Nov 8, 2019 | Posted by in GENERAL SURGERY | Comments Off on Effector Mechanisms of T Cell–Mediated Immunity: Functions of T Cells in Host Defense

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