The recognition of antigen and costimulators by T cells initiates an orchestrated set of responses that culminate in the expansion of the antigen-specific clones of lymphocytes and the differentiation of the naive T cells into effector cells and memory cells . Many of the responses of T cells are mediated by cytokines that are secreted by the T cells and act on the T cells themselves and on many other cells involved in immune defenses. Each component of the biologic responses of T cells is discussed next.

Secretion of Cytokines and Expression of Cytokine Receptors

In response to antigen and costimulators, T lymphocytes, especially CD4+ T cells, rapidly secrete the cytokine IL-2. We have already discussed cytokines in innate immune responses, which are produced mainly by dendritic cells and macrophages . In adaptive immunity, cytokines are secreted by T cells, mainly CD4+ cells. Because most of these cytokines are produced by effector T cells and serve diverse roles in host defense.

IL-2 is produced within 1 to 2 hours after activation of CD4+ T cells. Activation also transiently increases the expression of the high-affinity IL-2 receptor, thus rapidly enhancing the ability of the T cells to bind and respond to IL-2 (Fig. 1). The receptor for IL-2 is a three-chain molecule. Naive T cells express two signaling chains, β and γ, which constitute the low-affinity receptor for IL-2, but these cells do not express the α chain (CD25) that enables the receptor to bind IL-2 with high affinity. Within hours after activation by antigens and costimulators, the T cells produce the α chain of the receptor, and now the complete IL-2 receptor is able to bind IL-2 strongly. Thus, IL-2 produced by antigen-stimulated T cells preferentially binds to and acts on the same T cells, an example of autocrine cytokine action.

The principal functions of IL-2 are to stimulate the survival and proliferation of T cells, resulting in an increase in the number of the antigen-specific T cells; because of these actions, IL-2 was originally called T cell growth factor. The high-affinity IL-2 receptor is constitutively expressed in regulatory T cells, so these cells are very sensitive to IL-2. In fact, IL-2 is essential for the maintenance of regulatory T cells and thus for controlling immune responses, as we discuss in Chapter 9.  Activated CD8+ T cells and natural killer (NK) cells express the low-affinity βγ receptor and respond to higher concentrations of IL-2.

Fig1. Role of interleukin-2 and IL-2 receptors in T cell proliferation. Naive T cells express the low- affinity IL-2 receptor (IL-2R) complex, made up of the β and γc chains (γc designates common γ chain, so called because it is a component of receptors for several cytokines). On activation by antigen recognition and costimulation, the cells produce IL-2 and express the α chain of the IL-2R (CD25), which associates with the β and γc chains to form the high-affinity IL-2 receptor. Binding of IL-2 to its receptor initiates proliferation of the T cells that recognized the antigen. APC, Antigen-presenting cell.

Clonal Expansion

T lymphocytes activated by antigen and costimulation begin to proliferate within 1 or 2 days, resulting in expansion of antigen-specific clones (Fig.2). This expansion quickly provides a large pool of antigen- specific lymphocytes from which effector cells can be generated to combat infection.

The magnitude of clonal expansion is remarkable, especially for CD8+ T cells. Before infection, the frequency of CD8+ T cells specific for any one microbial protein antigen is approximately 1 in 105 or 1 in 106 lymphocytes in the body. At the peak of some viral infections, possibly within a week after the infection, as many as 10% to 20% of all the lymphocytes in the lymphoid organs may be specific for that virus. This means that the numbers of cells in antigen-specific clones have increased by more than 10,000-fold, with an estimated doubling time of approximately 6 hours. This enormous expansion of T cells specific for a microbe is not accompanied by a detectable increase in bystander cells that do not recognize that microbe.

The expansion of CD4+ T cells appears to be 100 fold to 1000-fold less than that of CD8+ cells. This difference may reflect differences in the functions of the two types of T cells. CD8+ CTLs are effector cells that kill infected and tumor cells by direct contact, and many CTLs may be needed to kill large numbers of infected or tumor cells. By contrast, each CD4+ effector cell secretes cytokines that activate many other effector cells, so a relatively small number of cytokine producers may be sufficient.

Fig2. Expansion and decline of T cell responses. The numbers of CD4+ and CD8+ T cells specific for various antigens in inbred mice and the clonal expansion and contraction during immune responses are illustrated. The numbers are approximations based on studies of model microbial and other antigens in inbred mice; in humans, the numbers of lymphocytes are approximately 1000-fold greater.

Differentiation of Naive T Cells

into Effector Cells Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections and some cancers. This process of differentiation is the result of changes in gene expression, such as the activation of genes encoding cytokines (in CD4+ T cells) or cytotoxic proteins (in CD8+ CTLs). It begins in con cert with clonal expansion, and differentiated effector cells appear within 3 or 4 days after exposure to microbes. Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines. The subsets of T cells that are distinguished by their cytokine profiles are named Th1, Th2, and Th17 (Fig. 3). Many of these cells leave the peripheral lymphoid organs and migrate to sites of infection, where their cytokines recruit other leukocytes that destroy the infectious agents. Other differentiated CD4+ T cells remain in the lymphoid organs and migrate into lymphoid follicles, where they further differentiate into T follicular helper cells and help B lymphocytes to produce antibodies. As we discuss in Chapters 6 and 7, CD4+ helper T cells activate phagocytes and B lymphocytes through the actions of the plasma membrane protein CD40L and secreted cytokines. In addition, the interaction of CD40L on T cells with CD40 on dendritic cells increases the expression of costimulators on these APCs and the production of T cell–stimulating cytokines, thus providing a positive feedback (amplification) mechanism for APC-induced T cell activation. Effector cells of the CD8+ lineage acquire the ability to kill infected and tumor cells.

Fig3. Development of effector CD4+ T cells. When naive CD4+ T cells are activated in secondary lymphoid organs, they proliferate and differentiate into effector cells. Some of the effectors (the Th1, Th2, and Th17 populations) mostly exit the lymphoid organ and function to eradicate microbes in peripheral tissues. Other differentiated cells, called follicular helper T (Tfh) cells, remain in the lymphoid organ and help B cells to produce potent antibodies.

Development of Memory T Lymphocytes

A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells. These cells are a pool of lymphocytes that are induced by microbes and are ready to respond rapidly if the microbe returns. We do not know what factors determine whether the progeny of antigen-stimulated lymphocytes will differentiate into effector cells or memory cells. Memory cells have several important characteristics.

• Memory cells survive even after the infection is eradicated and antigen is no longer present. Certain cytokines, including IL-7 and IL-15, which are produced by stromal cells in tissues, may serve to keep memory cells alive and cycling slowly.

• Memory T cells may be rapidly induced to produce cytokines or kill infected cells on encountering the antigen that they recognize. These cells do not perform any effector functions until they encounter antigen, but once activated, they respond much more vigorously and rapidly than do naive lymphocytes.

 • Memory T cells can be found in lymphoid organs, in various peripheral tissues, especially mucosa and skin, and in the circulation. They can be distinguished from naive and effector cells by several criteria . A subset of memory T cells, called central memory cells, populate lymphoid organs and are responsible for rapid clonal expansion after reexposure to antigen. Another subset, called effector memory cells, localize in mucosal and other peripheral tissues and mediate rapid effector functions on reintroduction of antigen to these sites. A third subset, called tissue-resident memory cells, reside in the skin and mucosal tissues and may be incapable of entering the circulation. They mediate rapid secondary responses to antigens encountered in tissues. 

Memory T cells can likely be activated in lymphoid and nonlymphoid tissues, and their activation, unlike that of naive T cells, does not require high levels of costimulation or antigen presentation by dendritic cells. In fact, various APCs, including B cells, may be capable of activating memory T cells.