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Activation-induced apoptosis of autoreactive and alloreactive T lymphocytes in the target organ as a major mechanism of tolerance Pender MPImmunol Cell Biol 1999[Jun]; 77 (3): 216-23Normal individuals have mature T lymphocytes that are capable of reacting to self-antigens and can be activated by cross-reacting environmental antigens. The mechanism that maintains immune tolerance and prevents these activated autoreactive T cells from causing autoimmune disease is unclear. We have previously hypothesized that activation-induced apoptosis of previously activated autoreactive T cells in the target organ is a major mechanism for maintaining tolerance. Here I review the current evidence to support this hypothesis. It is proposed that when activated autoreactive T cells enter the target organ, they are reactivated mainly by non-professional antigen-presenting cells (APC) and deleted by activation-induced apoptosis through the Fas (CD95) pathway before producing significant target organ damage. This apoptosis occurs because the reactivated T cells do not receive sufficient costimulation from the non-professional APC to up-regulate their expression of Bcl-2-related anti-apoptotic proteins, which inhibit the CD95 pro-apoptotic pathway. This is in contrast to the situation in peripheral lymphoid organs, where reactivation of T cells by professional APC results in sufficient costimulation-induced up-regulation of Bcl-2-related proteins to inhibit the CD95 pathway and allow T cell proliferation and survival as memory T cells. Activation-induced apoptosis of alloreactive T cells in allografts can similarly account for spontaneous allograft acceptance, as occurs after MHC-mismatched liver transplantation.|Animals[MESH]|Antigen-Presenting Cells/immunology[MESH]|Apoptosis/*immunology[MESH]|Autoimmune Diseases/immunology[MESH]|Autoimmunity/physiology[MESH]|Encephalomyelitis, Autoimmune, Experimental/immunology[MESH]|Humans[MESH]|Immune Tolerance/*physiology[MESH]|Lymphocyte Activation[MESH]|Multiple Sclerosis/immunology[MESH]|T-Lymphocytes/*immunology[MESH]|fas Receptor/immunology[MESH] |
