Fas-independent death of activated CD4(+) T lymphocytes induced by CTLA-4 crosslinking.
The CTLA-4 receptor is a critical inhibitory regulator of T cell proliferation and effector function. However, the mechanisms through which CTLA-4 modulates the activation of T cells remain uncertain. Initial studies, using activated human T cells, have suggested that CTLA-4 crosslinking may induce apoptosis. However, more recent experiments have demonstrated that crosslinking of the CTLA-4 receptor on the surface of resting murine T cells blocks cell cycle progression without inducing apoptosis. Here we provide evidence that CTLA-4 crosslinking on the surface of activated murine CD4(+) T lymphocytes leads to death of a substantial fraction of the cells whereas in resting CD4(+) T cells the same stimulation conditions induce cell cycle arrest without apoptosis. Cell death induced by CTLA-4 stimulation occurs independently of Fas and therefore may involve a novel pathway. CTLA-4-mediated apoptosis may be a means of terminating the function of previously stimulated T cells. Exploitation of this mechanism also may provide a therapeutic strategy to eliminate alloreactive or autoreactive T cells.
Department of Immunology, Imperial College School of Medicine and Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
P
P
Scheipers
H
H
Reiser
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D060908:CTLA-4 Antigen; D002453:Cell Cycle; D003208:Concanavalin A / Q000494:pharmacology; D003432:Cross-Linking Reagents; D006801:Humans; D018796:Immunoconjugates; D007167:Immunotherapy; D066298:In Vitro Techniques; D007399:Interphase; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D019014:fas Receptor / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D003432:Cross-Linking Reagents; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D019014:fas Receptor; D003208:Concanavalin A; D000069594:Abatacept