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. 1). Naive T cells express antigen receptors and coreceptors that function in recognizing cells harboring microbes, but naïve 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 anti gens.

Fig1. 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. 2). 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. 2).

Fig2. 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.

• 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 pro mote 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.

 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.

Naive and effector T cells have different patterns of circulation and migration through tissues, which are critical for their different roles in immune responses.

 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 . 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.