ventional α:β T-cell receptors and are selected in the thymus by high-affinity binding to MHC molecules containing self-peptides. It is not currently known whether they are activated to express their regulatory function in the periphery by the same self ligands that selected them in the thymus or by other self or non-self antigens. Multiple mechanisms appear to contribute to the ability of T cells to inhibit responses of other T cells, but principal among these are interactions with antigen-presenting cells that interfere with the capacity of antigen-presenting cells to provide activating signals. The expression of high levels of CTLA-4 on the surface of natural T cells is thought to permit them to compete for B7 expressed by antigen-presenting cells, thereby preventing adequate co-stimulation of naive T cells. Indeed, it has been proposed that CTLA4 expressed on T cells can physically remove B7 molecules from the surface of antigen-presenting cells, thereby depleting them of co-stimulatory activity. Similarly, by expressing CD25, and thus the high-affinity receptor for IL-2, and lacking the ability to produce IL-2, T cells appear to sequester IL-2 from naive T cells, which lack CD25 expression until fully activated.
Other functions of T cells are mediated by their production of immunosup pressive cytokines. TGF-β produced by T cells can inhibit T-cell prolifera tion (see Fig. 9.34). IL-10, which is produced by T cells late in an immune response, inhibits the expression of MHC molecules and co-stimulatory molecules by antigen-presenting cells. As a means of limiting the responses of effector T cells, IL-10 also inhibits the production of pro-inflammatory cytokines by antigen-presenting cells. For example, IL-10 potently inhibits the production of IL-12 and IL-23 by antigen-presenting cells and thus impairs their ability to promote the differentiation and maintenance of TH1 and TH17 cells, respectively. The critical role of T cells in immune regulation is highlighted by several autoimmune syndromes (described in Chapter 15) that are caused by deficiency in different aspects of T cell function.
Although they differentiate in secondary lymphoid tissues after export from the thymus, induced T cells also express FoxP3 and share most of the phenotypic and functional features of natural T cells. A major function of iT cells is the prevention of inflammatory immune responses to the commensal microbiota, particularly microbes resident in mucosal tissues such as the intestines. Here, iT cells appear to be the dominant source of IL-10, deficiency of which causes inflammatory bowel disease, an immune-mediated disease of the intestines characterized by chronic reactivity against antigens of the intestinal microbiota (see also Section 15-23). As will be discussed in more detail in Chapter 12, the differentiation of induced T cells in the intestines is favored by the presence of antigen-presenting cells that produce retinoic acid, which is derived from vitamin A. Retinoic acid produced by intestinal dendritic cells acts with TGF-β to induce T differentiation while suppressing the differentiation of TH17 cells (see Fig. 9.33). The antagonistic balance of retinoic acid and IL-6 therefore