Activation-induced apoptosis of autoreactive and alloreactive T lymphocytes in the target organ as a major mechanism of tolerance

Normal individuals have mature T lymphocytes that are capable of reacting t o self-antigens and can be activated by cross-reacting environmental antige ns. The mechanism that maintains immune tolerance and prevents these activa ted autoreactive T cells from causing autoimmune disease is unclear. We hav e previously hypothesized that activation-induced apoptosis of previously a ctivated autoreactive T cells in the target organ is a major mechanism for maintaining tolerance. Here I review the current evidence to support this h ypothesis. It is proposed that when activated autoreactive T cells enter th e target organ, they are reactivated mainly by non-professional antigen-pre senting 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-apopt otic pathway. This is in contrast to the situation in peripheral lymphoid o rgans, where reactivation of T cells by professional APC results in suffici ent costimulation-induced up-regulation of Bcl-2-related proteins to inhibi t the CD95 pathway and allow T cell proliferation and survival as memory T cells. Activation-induced apoptosis of alloreactive T cells in allografts c an similarly account for spontaneous allograft acceptance, as occurs after MHC-mismatched liver transplantation.