The Caspase 8 Inhibitor c-FLIP_L Modulates T-Cell Receptor-Induced Proliferation but Not Activation-Induced Cell Death of Lymphocytes

Abstract

The caspase 8 inhibitor c-FLIP_L can act in vitro as a molecular switch between cell death and growth signals transmitted by the death receptor Fas (CD95). To elucidate its function in vivo, transgenic mice were generated that overexpress c-FLIP_L in the T-cell compartment (c-FLIP_L Tg mice). As anticipated, FasL-induced apoptosis was inhibited in T cells from the c-FLIP_L Tg mice. In contrast, activation-induced cell death of T cells in c-FLIP_L Tg mice was unaffected, suggesting that this deletion process can proceed in the absence of active caspase 8. Accordingly, c-FLIP_L Tg mice differed from Fas-deficient mice by showing no accumulation of B220⁺ CD4⁻ CD8⁻ T cells. However, stimulation of T lymphocytes with suboptimal doses of anti-CD3 or antigen revealed increased proliferative responses in T cells from c-FLIP_L Tg mice. Thus, a major role of c-FLIP_L in vivo is the modulation of T-cell proliferation by decreasing the T-cell receptor signaling threshold.

We thank Anne Wilson for her generous gifts of Abs and helpful discussions.

S.M.A.L. is a fellow of the Dutch Cancer Society. This work was supported in part by grants AI36333 and AI45666 from the National Institutes of Health (R.C.B.).