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.