Peripheral tolerance to self proteins is induced because these antigens are presented to T lymphocytes under conditions that do not allow effective immune responses to develop, or because the responses of the specific T cells are tightly regulated. The two principal mechanisms of peripheral tolerance are activation-induced cell death (AICD) and anergy. In CD4+ T lymphocytes, AICD is induced by repeated stimulation, with high levels of interleukin (IL)-2 production. Under these conditions, the T cells co-express Fas (CD95) and Fas ligand (FasL), and engagement of Fas triggers apoptotic death of the T cells. Mice with defects in Fas, FasL, IL-2R alpha or beta chain exhibit defects in AICD and develop autoimmune disease. The induction of T cell anergy is dependent on the recognition of B7 co-stimulators by the inhibitory T cell counter-receptor, CTLA-4. Failure of anergy is the likely basis for the fatal autoimmune disease of CTLA-4 knockout mice. The single-gene defects that result in autoimmunity are all defects in lymphocyte regulation, indicating that tolerance is often maintained by the control of lymphocyte responses to self antigen. The existence of distinct pathways of T cell tolerance suggest that different types of antigens induce tolerance by distinct mechanisms.