Regulation of Fas ligand-induced apoptosis by TNF

Fas ligand (FasL, CD95L) expression helps control inflammatory reactions in immune privileged sites such as the eye. Cellular activation is normally r equired to render lymphoid cells sensitive to FasL-induced death; however, both activated and freshly isolated Fas(+) lymphoid cells are efficiently k illed in the eye. Thus, we examined factors that might regulate cell death in the eye. TNF levels rapidly increased in the eye after the injection of lymphoid cells, and these cells underwent apoptosis within 24 h. Coinjectio n of anti-TNF Ab with the lymphoid cells blocked this cell death. Furthermo re, TNFR2(-/-) T cells did not undergo apoptosis in the eyes of normal mice , while normal and TNFR1(-/-) T cells were killed by apoptosis. In vitro, T NF enhanced the Fas-mediated apoptosis of unactivated T cells through decre ased intracellular levels of FLIP and increased production of the pro-apopt otic molecule Bax. This effect was mediated through the TNFR2 receptor. In vivo, intracameral injection of normal or TNFR1(-/-) 2,4,6-trinitrophenyl-c oupled T cells into normal mice induced immune deviation, but TNFR2(-/-) 2, 4,6-trinitrophenyl-coupled T cells were ineffective. Collectively, our resu lts provide evidence of a role for the p75 TNFR in cell death in that TNF s ignaling through TNFR2 sensitizes lymphoid cells for Fas-mediated apoptosis . We conclude that there is complicity between apoptosis and elements of th e inflammatory response in controlling lymphocyte function in immune privil eged sites.