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

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Abstract
Normal 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.
Funding Information
  • National Health and Medical Research Council of Australia
  • National Multiple Sclerosis Society of Australia