T Cell –Mediated Immunity: Activation of T Lymphocytes

T lymphocytes perform multiple functions in defending against infections by various kinds of microbes. A major role for T lymphocytes is in cell-mediated immunity , which provides defense against infections by microbes that live and reproduce inside host cells. In all viral and some bacterial, fungal, and protozoan infections, microbes may find a haven inside cells, from where they must be eliminated by cell-mediated immune responses ( Fig. 5.1 ).

  • Many microbes are ingested by phagocytes as part of the early defense mechanisms of innate immunity and are killed by microbicidal mechanisms that are largely limited to phagocytic vesicles (to protect the cells themselves from damage by these mechanisms). However, some of these microbes have evolved to resist the microbicidal activities of phagocytes and are able to survive, and even replicate, in the vesicles of phagocytes. In such infections, T cells stimulate the ability of macrophages to kill the ingested microbes.

  • Some extracellular microbes, such as bacteria and fungi, are readily destroyed if they are phagocytosed, especially by neutrophils. Other extracellular pathogens, such as helminthic parasites, are destroyed by special types of leukocytes (eosinophils). In these infections, T cells provide defense by recruiting the leukocytes that destroy the microbes.

  • Some microbes, notably viruses, are able to infect and replicate inside a wide variety of cells, and parts of the life cycles of the viruses take place in the cytosol and nucleus. These infected cells often do not possess intrinsic mechanisms for destroying the microbes, especially outside vesicles. Even some phagocytosed microbes within macrophages can escape into the cytosol and evade the microbicidal mechanisms of the vesicular compartment. T cells kill the infected cells, thus eliminating the reservoir of infection.

Fig. 5.1

Types of intracellular microbes combated by T cell–mediated immunity.

A, Microbes may be ingested by phagocytes and may survive within vesicles (phagolysosomes) or escape into the cytosol, where they are not susceptible to the microbicidal mechanisms of the phagocytes. B, Viruses may infect many cell types, including nonphagocytic cells, and replicate in the nucleus and cytosol of the infected cells. Rickettsiae and some protozoa are obligate intracellular parasites that reside in nonphagocytic cells.

Other populations of T cells help B cells to produce antibodies as part of humoral immune responses (see Chapter 7 ). Although our emphasis in this chapter is on defense against infections, the principal physiologic function of the immune system, some T cells, especially CD8 + T cells, also destroy cancerous cells. This role of T cells is discussed in Chapter 10 .

Most of the functions of T lymphocytes—activation of phagocytes, killing of infected and tumor cells, and help for B cells—require that the T lymphocytes interact with other cells, which may be phagocytes, infected host cells, or B lymphocytes. Furthermore, the initiation of T cell responses requires that naive T cells recognize antigens displayed by dendritic cells, which capture antigens and concentrate them in lymphoid organs. Thus, T lymphocytes work by communicating with other cells. Recall that the specificity of T cells for peptides displayed by major histocompatibility complex (MHC) molecules ensures that the T cells can see and respond only to antigens associated with other host cells (see Chapters 3 and 4Chapter 3Chapter 4). This chapter discusses the way in which T lymphocytes are activated by recognition of cell-associated antigens and other stimuli. We address the following questions:

  • What signals are needed to activate T lymphocytes, and what cellular receptors are used to sense and respond to these signals?

  • How are the few naive T cells specific for any microbe converted into the large number of effector T cells that have specialized functions and the ability to eliminate diverse microbes?

  • What molecules are produced by T lymphocytes that mediate their communications with other cells, such as macrophages, B lymphocytes, and other leukocytes?

After describing here how T cells recognize and respond to the antigens of cell-associated microbes, in Chapter 6 , we discuss how these T cells function to eliminate the microbes.

Phases of T Cell Responses

Naive T lymphocytes recognize antigens in the peripheral (secondary) lymphoid organs, which initiates proliferation of the T cells and their differentiation into effector and memory cells, and the effector cells perform their functions when they are activated by the same antigens in any infected tissue ( Fig. 5.2 ). Naive T cells express antigen receptors and coreceptors that function in recognizing cells harboring microbes, but naive cells are incapable of performing the effector functions required for eliminating the microbes. Differentiated effector cells are capable of performing these functions, which they do at any site of infection. In this chapter, we focus on the initial responses of naive T cells to antigens. The development of effector T lymphocytes and their functions in cell-mediated immunity are described in Chapter 6 and the roles of helper T cells in antibody responses in Chapter 7 .

Fig. 5.2

Induction and effector phases of cell-mediated immunity.

Induction of response: Naive CD4 + T cells and CD8 + T cells recognize peptides that are derived from protein antigens and presented by dendritic cells (DCs) in peripheral lymphoid organs. The T lymphocytes are stimulated to proliferate and differentiate into effector cells, many of which enter the circulation. Some of the activated CD4 + T cells remain in the lymph node, migrate into follicles, and help B cells to produce antibodies (shown in Fig. 5.13 ). Migration of effector T cells and other leukocytes to site of antigen: effector T cells and other leukocytes migrate through blood vessels in peripheral tissues by binding to endothelial cells that have been activated by cytokines produced in response to infection in these tissues. T cell effector functions: CD4 + T cells recruit and activate phagocytes to destroy microbes, and CD8 + cytotoxic T lymphocytes (CTLs) kill infected cells.

The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps that result in an increase in the number of antigen-specific T cells and the conversion of naive T cells to effector and memory cells ( Fig. 5.3 ).

  • One of the earliest responses is the secretion of cytokines required for growth and differentiation and increased expression of receptors for various cytokines. The cytokine interleukin-2 (IL-2), which is produced by antigen-activated T cells, stimulates proliferation of these cells, resulting in a rapid increase in the number of antigen-specific lymphocytes, a process called clonal expansion.

  • The activated lymphocytes differentiate, resulting in the conversion of naive T cells into a population of effector T cells , which function to eliminate microbes.

  • Many of the effector T cells leave the lymphoid organs, enter the circulation, and migrate to any site of infection, where they can eradicate the infection. Some activated T cells may remain in the lymph node, where they provide signals to B cells that promote antibody responses against the microbes.

  • Some of the progeny of the T cells that have proliferated in response to antigen develop into memory T cells, which are long-lived, circulate or reside in tissues for years, and are ready to respond rapidly to subsequent exposure to the same microbe.

  • As effector T cells eliminate the infectious agent, the stimuli that triggered T cell expansion and differentiation also are eliminated. As a result, most of the cells in the greatly expanded clones of antigen-specific effector lymphocytes die, returning the system to a resting state, with only memory cells remaining from the immune response.

Fig. 5.3

Steps in the activation of T lymphocytes.

Naive T cells recognize major histocompatibility complex (MHC)-associated peptide antigens displayed on antigen-presenting cells and other signals (not shown). The T cells respond by producing interleukin-2 (IL-2) and expressing receptors for IL-2, leading to an autocrine pathway of cell proliferation. The result is expansion of the clone of T cells that are specific for the antigen. Some of the progeny differentiate into effector cells, which serve various functions in cell-mediated immunity, and memory cells, which survive for long periods. Other changes associated with activation, such as the expression of various surface molecules, are not shown. APC , Antigen-presenting cell; CTL , cytotoxic T lymphocyte; IL-2R , interleukin-2 receptor.

This sequence of events is common to both CD4 + and CD8 + T lymphocytes, although there are important differences in the properties and effector functions of CD4 + and CD8 + cells, as discussed in Chapter 6 .

Naive and effector T cells have different patterns of circulation and migration through tissues, which are critical for their different roles in immune responses . As discussed in previous chapters, naive T lymphocytes constantly recirculate through peripheral lymphoid organs searching for foreign protein antigens. The antigens of microbes are transported from the portals of entry of the microbes to the same regions of peripheral lymphoid organs through which naive T cells recirculate. In these organs, the antigens are processed and displayed by MHC molecules on dendritic cells, the antigen-presenting cells (APCs) that are the most efficient stimulators of naive T cells (see Chapter 3 ). When a T cell recognizes antigen, it is transiently arrested on the dendritic cell and it initiates an activation program. Activation results in proliferation and differentiation, and then the cells may leave the lymphoid organ and migrate preferentially to the inflamed tissue, the original source of the antigen. The control of this directed migration is discussed later in this chapter.

With this overview, we proceed to a description of the stimuli required for T cell activation and regulation. We then describe the biochemical signals that are generated by antigen recognition and the biologic responses of the lymphocytes.

Antigen Recognition and Costimulation

The initiation of T cell responses requires multiple receptors on the T cells recognizing their specific ligands on APCs ( Fig. 5.4 ).

  • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.

  • CD4 or CD8 coreceptors on the T cells bind to MHC molecules on the APC and work with the TCR complex to deliver activating signals.

  • Adhesion molecules strengthen the binding of T cells to APCs.

  • Molecules called costimulators, which are expressed on APCs after encounter with microbes, bind to costimulatory receptors on the naive T cells, thus promoting responses to infectious pathogens.

  • Cytokines amplify the T cell response and direct it along various differentiation pathways.

Fig. 5.4

Receptors and ligands involved in T cell activation and inhibition.

A, Major surface molecules of CD4 + T cells involved in the activation of these cells and their corresponding ligands on antigen-presenting cells. CD8 + T cells use most of the same molecules, except that the TCR recognizes peptide-class I MHC complexes, and the coreceptor is CD8, which recognizes class I MHC. CD3 is composed of three polypeptide chains, δ, ε, and γ, arranged in two pairs (δε and γε); we show CD3 as three chains. Immunoreceptor tyrosine-based activation motifs (ITAMs) are the regions of cytosolic tails of signaling proteins that are phosphorylated on tyrosine residues and become docking sites for other tyrosine kinases (see Fig. 5.10 ). Immunoreceptor tyrosine-based inhibitory motifs are the regions of signaling proteins that are sites for tyrosine phosphatases that counteract actions of ITAMs. B, Important properties of major surface molecules of T cells involved in functional responses. Cytokines and cytokine receptors are not listed here. The functions of most of these molecules are described in this chapter; the role of CTLA-4 and PD-1 in shutting off T cell responses is described in Chapter 9 . LFA-1 is an integrin involved in leukocyte binding to endothelium and other cells. APC, Antigen-presenting cell; ICAM-1, intercellular adhesion molecule 1; LFA-1 , leukocyte function–associated antigen 1; MHC , major histocompatibility complex; PD-1 , programmed death-1; TCR, T cell receptor.

The roles of these molecules in T cell responses to antigens are described next. Cytokines are discussed mainly in Chapter 6 .

Recognition of Peptide-MHC Complexes

The TCR for antigen and the CD4 or CD8 coreceptor together recognize complexes of peptide antigens and MHC molecules on APCs, and this recognition provides the initiating, or first, signal for T cell activation ( Fig. 5.5 ). The TCRs expressed on all CD4 + and CD8 + T cells consist of an α chain and a β chain, both of which participate in antigen recognition (see Fig. 4.7 ). (A small subset of T cells expresses TCRs composed of γ and δ chains, which do not recognize MHC-associated peptide antigens.) The TCR of a T cell specific for a foreign (e.g., microbial) peptide recognizes the displayed peptide and simultaneously recognizes residues of the MHC molecule located around the peptide-binding cleft. Every mature MHC-restricted T cell expresses either CD4 or CD8, both of which are called coreceptors because they bind to the same MHC molecules that the TCR binds and are required for initiation of signaling from the TCR complex. At the time when the TCR is recognizing the peptide-MHC complex, CD4 or CD8 binds the class II or class I MHC molecule, respectively, at a site separate from the peptide-binding cleft. As discussed in Chapter 3 , when protein antigens are ingested by APCs from the extracellular milieu into vesicles, these antigens are processed into peptides that are displayed by class II MHC molecules. In contrast, protein antigens present in the cytosol are processed by proteasomes into peptides displayed by class I MHC molecules. Thus, because of the specificity of the coreceptors for different classes of MHC molecules, CD4 + and CD8 + T cells recognize peptides generated through different protein processing pathways. The TCR and its coreceptor need to be engaged simultaneously to initiate the T cell response, and multiple TCRs likely need to be triggered for T cell activation to occur. Once these conditions are achieved, the T cell begins its activation program.

Fig. 5.5

Antigen recognition and signal transduction during T cell activation.

Different T cell molecules recognize antigen and deliver biochemical signals to the interior of the cell as a result of antigen recognition. The CD3 and ζ proteins are noncovalently attached to the T cell receptor (TCR) α and β chains by interactions between charged amino acids in the transmembrane domains of these proteins (not shown). The figure illustrates a CD4 + T cell; the same interactions are involved in the activation of CD8 + T cells, except that the coreceptor is CD8 and the TCR recognizes a peptide–class I MHC complex. APC, Antigen-presenting cell; ITAM, immunoreceptor tyrosine-based activation motifs; MHC, major histocompatibility complex.

The biochemical signals that lead to T cell activation are triggered by a set of proteins linked to the TCR that are part of the TCR complex and by the CD4 or CD8 coreceptor (see Fig. 5.5 ). In lymphocytes, antigen recognition and subsequent signaling are performed by different sets of molecules. The TCR αβ heterodimer recognizes antigens, but it is not able to transmit biochemical signals to the interior of the cell. The TCR is noncovalently associated with a complex of transmembrane signaling proteins including three CD3 proteins and a protein called the ζ chain. The TCR, CD3, and ζ chain make up the TCR complex. Although the α and β TCRs must vary among T cell clones in order to recognize diverse antigens, the signaling functions of TCRs are the same in all clones, and therefore the CD3 and ζ proteins are invariant among different T cells. The mechanisms of signal transduction by these proteins of the TCR complex are discussed later in the chapter.

T cells can also be activated by molecules that bind to the TCRs of many or all clones of T cells, regardless of the peptide-MHC specificity of the TCR. For instance, some microbial toxins may bind to the TCRs of many T cell clones and also bind to MHC class II molecules on APCs without occupying the peptide-binding cleft. By activating a large number of T cells, these toxins induce excessive cytokine release and cause systemic inflammatory disease. They are called superantigens because, like conventional antigens, they bind to MHC molecules and to TCRs, but to many more than typical antigens do.

Role of Adhesion Molecules in T Cell Responses

Adhesion molecules on T cells recognize their ligands on APCs and stabilize the binding of the T cells to the APCs . Most TCRs bind the peptide-MHC complexes for which they are specific with low affinity. To induce a response, the binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold. This stabilization function is performed by adhesion molecules on the T cells that bind to ligands expressed on APCs. The most important of these adhesion molecules belong to the family of heterodimeric (two-chain) proteins called integrins. The major T cell integrin involved in binding to APCs is leukocyte function–associated antigen 1 (LFA-1), whose ligand on APCs is called intercellular adhesion molecule 1 (ICAM-1).

On resting naive T cells, which are cells that have not previously recognized and been activated by antigen, the LFA-1 integrin is in a low-affinity state. Antigen recognition by a T cell increases the affinity of that cell’s LFA-1. Therefore, once a T cell sees antigen, it increases the strength of its binding to the APC presenting that antigen, providing a positive feedback loop. Integrin-mediated adhesion is critical for the ability of T cells to bind to APCs displaying microbial antigens. Integrins also play an important role in directing the migration of effector T cells and other leukocytes from the circulation to sites of infection. This process is described in Chapter 2 and later in this chapter.

Role of Costimulation in T Cell Activation

The full activation of T cells depends on the recognition of costimulators on APCs in addition to antigen ( Fig. 5.6 ). We have previously referred to costimulators as second signals for T cell activation. The name costimulator derives from the fact that these molecules provide stimuli to T cells that function together with stimulation by antigen.

Fig. 5.6

Role of costimulation in T cell activation.

Resting antigen-presenting cells (APCs) , which have not been exposed to microbes or adjuvants, may present peptide antigens, but they do not express costimulators and are unable to activate naive T cells. T cells that recognize antigen without costimulation may die or become unresponsive (tolerant) to subsequent exposure to antigen. Microbes, as well as cytokines produced during innate immune responses to microbes, induce the expression of costimulators, such as B7 molecules, on the APCs. The B7 costimulators are recognized by the CD28 receptor on naive T cells, providing signal 2. In conjunction with antigen recognition (signal 1), this recognition initiates T cell responses. Activated APCs also produce cytokines that stimulate the differentiation of naive T cells into effector cells (not shown). IL, Interleukin.

The best-defined costimulators for T cells are two homologous proteins called B7-1 (CD80) and B7-2 (CD86), both of which are expressed on APCs and whose expression is increased when the APCs encounter microbes. These B7 proteins are recognized by a receptor called CD28, which is expressed on most T cells. Different members of the B7 and CD28 families serve to stimulate or inhibit immune responses ( Fig. 5.7 ). The binding of CD28 on T cells to B7 on the APCs generates signals in the T cells that work together with signals generated by TCR recognition of antigen presented by MHC proteins on the same APCs. CD28-mediated signaling is essential for the responses of naive T cells; in the absence of CD28:B7 interactions, antigen recognition by the TCR is insufficient for initiating T cell responses. The requirement for costimulation ensures that naive T lymphocytes are activated maximally by microbial antigens and not by harmless foreign substances or by self antigens, because, as stated previously, microbes stimulate the expression of B7 costimulators on APCs.

Nov 8, 2019 | Posted by in GENERAL SURGERY | Comments Off on T Cell –Mediated Immunity: Activation of T Lymphocytes

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