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In contrast to humoral immune responses that are mediated by antibody, cell‐mediated responses are T cell mediated. However, this is an oversimplified definition since the effector cell responsible for the elimination of a foreign antigen such as a pathogenic microbe can be an activated T cell expressing a pathogen‐specific TCR or a phagocytic cell that gets activated by innate receptors that they express and the cytokines produced by activated T cells (Figure 1.4). Unlike B cells, which produce soluble antibody that circulates to bind its specific antigens, each T cell, bearing approximately 100,000 identical antigen receptors (TCRs), circulates directly to the site of antigen expressed on APCs and interacts with these cells in a cognate (cell‐to‐cell) fashion (see Chapters 8 and 10). Activated T cells do release soluble mediators such as cytokines but these are not antigen specific.

There are several phenotypically distinct subpopulations of T cells, each of which may have the same specificity for an antigenic determinant (epitope), although each subpopulation may perform different functions. This is somewhat analogous to the different classes of immunoglobulin molecules, which may have identical specificity but different biological functions. Several major subsets of T cells exist: helper T cells (T_H cells), which express molecules called CD4, and cytotoxic T cells (T_C cells), which express CD8 molecules on their surface. Another population of T cells that possesses suppressor activity is the T regulatory (Treg) cells.

The functions ascribed to the various subsets of T cells include the following.

 B‐cell help. TH helper cells cooperate with B cells to enhance the production of antibodies. Such T cells function by releasing cytokines, which provide various activation signals for the B cells. As mentioned earlier, cytokines are soluble substances or mediators that can regulate proliferation and differentiation of B cells, among other functions. Additional information about cytokines is presented in Chapter 11.

 Inflammatory effects. On activation, certain TH cells release cytokines that induce the migration and activation of monocytes and macrophages, leading to inflammatory reactions (Chapter 15).

 Cytotoxic effects. As illustrated in Figure 1.1, T cells differentiate into subpopulations commonly defined as TH helper cells (a.k.a. TH cells), discussed below, and TC cytotoxic cells (TC cells). As the name implies, the latter cells have cytotoxic effects on other cells, a phenomenon that will be discussed further in later chapters. Upon contact with a specific target cell, TC cells are able to deliver a lethal hit, leading to the death of the latter. TC cells all express membrane molecules called CD8 and are, therefore, CD8+ cells.Figure 1.4. Antigen receptors expressed as transmembrane molecules on B and T lymphocytes.

 Regulatory effects. In contrast with TC cells, TH cells play a significant role in regulating immune responses. The other distinguishing feature of TH cells is their expression of membrane molecules called CD4 (hence, they are CD4+ cells). They can be further subdivided into different functional subsets that are commonly defined by the cytokines they release. As you will learn in subsequent chapters, these subsets (e.g., TH1, TH2) have distinct regulatory properties that are mediated by the cytokines they release (Chapter 11). TH1 cells can negatively cross‐regulate TH2 cells and vice versa. Another population of regulatory T cells, the Treg cells, co‐express CD4 and a molecule called CD25 (CD25 is part of a cytokine receptor known as the interleukin‐2 receptor α chain). The regulatory activity of these CD4+/CD25+ cells and their role in actively suppressing autoimmunity are discussed in Chapter 12.

 Cytokine effects. Cytokines produced by each of the T‐cell subsets (principally TH cells) exert numerous effects on many cells, lymphoid and nonlymphoid. Thus directly or indirectly, T cells communicate and collaborate with many cell types.

For many years, immunologists recognized that cells activated by antigen manifest a variety of effector phenomena. It is only in the past few decades that they began to appreciate the complexity of events that take place in activation by antigen and communication with other cells. We know today that just mere contact of the TCR with antigen is not sufficient to activate the cell. In fact, at least two signals must be delivered to the antigen‐specific T cell for activation to occur. Signal 1 involves the binding of the TCR to antigen, which must be presented in the appropriate manner by APCs. Signal 2 involves co‐stimulators that include certain cytokines such as interleukin (IL)‐1, IL‐4, and IL‐6 (Chapter 11) as well as cell‐surface molecules expressed on APCs, such as CD40 and CD86. The term co‐stimulator has been broadened to include stimuli such as microbial products (infectious nonself) and damaged tissue (Matzinger’s “danger hypothesis”) that will enhance signal 1 when that signal is relatively weak.

Once T cells are optimally signaled for activation, a series of events takes place and the activated cell synthesizes and releases cytokines. In turn, these cytokines come in contact with appropriate cell surface receptors on different cells and exert their effect on these cells.