In immune responses, T lymphocytes have to recognize the same antigen at two stages: first to initiate the response and later to perform effector functions. Antigen activates naive cells to proliferate and differentiate into effector and memory cells. The effector T cells are then activated by the same antigen to perform the functions that lead to elimination of the source of the antigen (infected cells or tumors). As we discuss later, the requirements for these two activation events differ in terms of the APCs involved and the other signals needed.
The initial activation of naive T lymphocytes occurs mainly in secondary (peripheral) lymphoid organs, through which these cells normally circulate and where foreign antigens are concentrated and presented by mature dendritic cells (DCs) (Fig. 1). Clones of T lymphocytes, each with a different specificity, are generated in the thymus before antigen exposure. Naive T lymphocytes, which have not previously responded to antigens, circulate throughout the body in a resting state, and they acquire powerful functional capabilities only after they are activated. The activation of naive T lymphocytes occurs in specialized regions of lymph nodes, spleen, and mucosal lymphoid tissues, where naive lymphocytes interact with DCs that have captured antigens from tissues or blood.
Fig1. Activation of naive and effector T cells by antigens. Antigens that are transported by dendritic cells (DCs) to lymph nodes are recognized by naive T lymphocytes that recirculate through these lymph nodes. The T cells are activated by antigens presented by the DCs to differentiate into effector cells, which may remain in the lymphoid organs to help B lymphocytes or migrate to sites of infection, where they are again activated by antigens and perform their various functions, such as macrophage activation.
Antigen recognition together with other activating stimuli induce several biologic responses in T cells: cytokine secretion and increased cytokine receptor expression; proliferation, leading to an increase in the numbers of cells in the antigen-specific clones (called clonal expansion); and differentiation of the naive cells into effector and memory lymphocytes (Fig. 2). The process of T-cell activation is associated with changes in the expression of numerous surface molecules, some of which are involved in trafficking of T cells and others play important roles in inducing and regulating T-cell responses. APCs not only display antigens but also express surface molecules and secrete cytokines that affect the magnitude and nature of the T-cell response.
Fig2. Sequence of events in T-cell responses. Antigen recognition by T cells induces cytokine (e.g., interleukin-2 [IL-2]) secretion, particularly in CD4+ T cells, clonal expansion as a result of cell proliferation, and differentiation of the T cells into effector cells or memory cells. In the effector phase of the response, the effector CD4+ T cells respond to antigen by producing cytokines that have several actions, such as the recruitment and activation of leukocytes and activation of B lymphocytes, while CD8+ CTLs respond by killing other cells and secreting inflammatory cytokines. APC, Antigen-presenting cell; CTL, cytotoxic T lymphocyte; TCR, T-cell receptor.
Proliferation and differentiation of T cells are regulated by several feedback mechanisms. For example, activated T cells deliver signals back to the APCs, further increasing the APCs’ ability to activate T cells in a positive feedback loop. At the same time, some surface molecules expressed on activated T cells as well as cytokines secreted by these cells inhibit further activation, and these negative feedback mechanisms serve to establish safe limits to the response.
Effector T cells recognize antigens in peripheral nonlymphoid tissues or in lymphoid organs and are activated to perform functions that contribute to the elimination of microbes, and, in disease states, induce tissue damage. Whereas naive cells are activated mainly in secondary lymphoid organs, differentiated effector cells may respond to antigens and carry out their functions in any tissue (see Fig. 1). The process of differentiation from naive to effector cells gives the cells the capacity to perform specialized functions and the ability to migrate to any site of infection or inflammation. At these sites, the effector cells again encounter the antigen for which they are specific and respond in ways that serve to eliminate the source of the anti gen. Effector CD4+ T cells, called helper T cells, can recognize antigens of microbes ingested by macrophages or B cells and activate these cells. Upon antigen-induced activation, the CD4+ T cells secrete cytokines and express cell surface molecules that can activate the macrophages or B cells. These helper T cells are classified into subpopulations on the basis of their cytokine pro files and functions (see Chapter 10). Some of the CD4+ effector T cells activate macrophages to kill phagocytosed microbes; others secrete cytokines that recruit different types of leukocytes, such as eosinophils and neutrophils, which destroy different types of pathogens; and yet others remain in lymphoid organs and help B cells differentiate into antibody-secreting plasma cells and memory cells. Effector CD8+ T cells, called cytotoxic T lymphocytes (CTLs), can recognize antigens in infected or tumor cells and directly kill those cells. CTLs also secrete cytokines that activate macrophages and induce inflammation.
Memory T cells that are generated by T-cell activation are long-lived and have an enhanced ability to react against the antigen. These cells are present in the recirculating lymphocyte pool and reside in mucosal tissues and the skin and in lymphoid organs. After a T-cell response wanes, there are many more memory cells of the responding clone than there were naive T cells before the response. These memory cells respond rapidly to subsequent encounters with the antigen and generate new effector cells that can eliminate the antigen.
T-cell responses decline after the antigen is eliminated. This process of contraction (numerical reduction of activated T cells) is important for returning the immune system to a state of equilibrium, or homeostasis. It occurs mainly because the majority of antigen-activated effector T cells die by apoptosis after performing their functions. One reason for this is that as the antigen is eliminated, lymphocytes are deprived of survival stimuli that are normally provided by the antigen and by the costimulators and cytokines produced during inflammatory reactions associated with infections and other types of antigen exposure. In addition, inhibitory mechanisms activated by antigen recognition function to control the magnitude and duration of the response.
With this overview, we will proceed to a discussion of the signals required for T-cell activation and the steps in the responses of CD4+ and CD8+ T cells. We will conclude with a discussion of memory cells and the decline of immune responses.
