Mp. Pender, Activation-induced apoptosis of autoreactive and alloreactive T lymphocytes in the target organ as a major mechanism of tolerance, IMM CELL B, 77(3), 1999, pp. 216-223
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.