Journal
CELL REPORTS
Volume 18, Issue 1, Pages 12-22Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.12.022
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Funding
- President's Initiative and Networking Fund of the Helmholtz Association of German Research Centers [VH-GS-202]
- Fritz-Thyssen-Stiftung [Az. 10.13.1.200]
- Deutsche Forschungsgemeinschaft [SCHM1586/6-1]
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Regulatory T (Treg) cells are critical for the shutdown of immune responses and have emerged as valuable targets of immunotherapies. Treg cells can rapidly proliferate; however, the homeostatic processes that limit excessive Treg cell numbers are poorly understood. Here, we show that, compared to conventional T cells, Treg cells have a high apoptosis rate ex vivo correlating with low c-FLIP expression. Treg-specific deletion of c-FLIP in mice resulted in fatal autoimmune disease of a scurfy-like phenotype characterized by absent peripheral Treg cells, activation of effector cells, multi-organ immune cell infiltration, and premature death. Surprisingly, blocking CD95L did not rescue Treg survival in vivo, suggesting additional survival functions of c-FLIP in Treg cells in addition to its classical role in the inhibition of death receptor signaling. Thus, our data reveal a central role for c-FLIP in Treg cell homeostasis and prevention of autoimmunity.
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