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on dendritic cells, B cells, and other cell populations. ICOS plays an essential role in T cell-dependent antibody responses, particularly in the germinal center reaction. It is required for the development and activation of follicular helper T cells, which provide critical activating signals to B cells in germinal centers (see Chapter 11).

The outcome of T cell activation is influenced by a balance between engagement of activating and inhibitory receptors of the CD28 family. The inhibitory receptors of the CD28 family are CTLA-4 (cytotoxic T lymphocyte antigen 4, so called because this molecule was the fourth protein identified in a search for molecules expressed in CTLs) and PD-1 (programmed death 1). (The names of these two proteins do not accurately reflect their distribution or function.) The concept that a balance between activating and inhibitory receptors controls the magnitude of responses in the immune system was mentioned in Chapter 4 in the context of natural killer (NK) cells (see Fig. 4-6, Chapter 4). A similar idea is applicable to responses of T and B lymphocytes, although the receptors involved are quite different. Because the inhibitory receptors CTLA-4 and PD-1 are involved in the phenomenon of tolerance, and abnormalities in their expression or function cause autoimmune diseases, we will discuss them in more detail in Chapter 14 in the context of tolerance and autoimmunity. Suffice it to say here that CD28 and CTLA-4 provide an illustrative example of two receptors that recognize the same ligands (the B7 molecules) but have opposite functional effects on T cell activation. CTLA-4 is a high-affinity receptor for B7, and it has been postulated that it is engaged when B7 levels on APCs are low (as on resting APCs displaying self antigens or APCs that are no longer exposed to microbes, after the microbes are cleared and the innate immune response subsides). CD28 has a 20- to 50-fold lower affinity for B7, and it may be engaged when B7 levels are relatively high (e.g., on exposure to microbes and innate immune responses). According to this model, the level of B7 expression on APCs influences the relative engagement of CD28 or CTLA-4, and this in turn determines if responses are initiated or terminated. Once engaged, CTLA-4 may competitively inhibit access of CD28 to B7 molecules on APCs, remove B7 from the surface of APCs, or deliver inhibitory signals that block activating signals from the TCR and CD28.

Other Costimulatory Pathways

Many other T cell surface molecules, including CD2 and integrins, have been shown to deliver costimulatory signals in vitro, but their physiologic role in promoting T cell activation is less clear than that of the CD28 family. We have discussed the functions of CD2 family proteins in Chapter 7 and of integrins in Chapter 3. Several other receptors that belong to the large tumor necrosis factor (TNF) receptor (TNFR) superfamily and their ligands, which are homologous to TNF, have been shown to stimulate and to inhibit T cells under various experimental conditions. The roles of these proteins in controlling normal and pathologic immune responses remain areas of active investigation.

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