Immunological Tolerance—T Cells

Abstract T lymphocytes are essential guardians against a plethora of pathogens and are thus characterized by an unprecedented diversity for antigen recognition. Their repertoire diversity is achieved by an elaborate, semirandom rearrangement of the genes encoding their respective antigen-specific receptors which inevitably generates many T cells that recognize not only foreign and potentially harmful antigens, but also the body’s own components. Therefore to deal with this problem and to prevent autoimmune destruction, the immune system has evolved a comprehensive network of several complementary mechanisms that are guided by four major principles to ensure tolerance to the body’s own antigens: (1) complete physical elimination of the self-reactive T-cell clone from the repertoire (clonal deletion), (2) conversion of the self-reactive clone into a tolerogenic and/or harmless T-cell subtype (anergy, phenotype skewing), (3) prevention of T-cell encounter with its specific self-antigen in the immune periphery (ignorance, antigen sequestering), and (4) prevention of clonal expansion or reactivation upon self-antigen (re)encounter (immunosuppression, T-cell intrinsic inhibitory mechanisms). In this chapter, we shall try to provide a fresh look at these key concepts and mechanisms underlying the establishment, maintenance, and breakdown of T-cell tolerance to the body’s own components.