c-FLIP Expression in Foxp3-Expressing Cells Is Essential for Survival of Regulatory T Cells and Prevention of Autoimmunity

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Carlos Plaza-Sirvent, Marc Schuster, Yvonne Neumann, Ulrike Heise, Marina C. Pils, Klaus Schulze-Osthoff, Ingo Schmitz
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.

Graphical abstract

Teaser

The mechanisms regulating homeostasis of regulatory T (Treg) cells are incompletely understood. Plaza-Sirvent et al. demonstrate that expression of the caspase-8-inhibitor c-FLIP is essential for Treg survival and prevention of autoimmunity because mice lacking c-FLIP in this cell type die early on due to fatal autoimmune disease.


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