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

• Published in: Cell reports (Cambridge) 2017-01, Vol.18 (1), p.12-22
• Main Authors: Plaza-Sirvent, Carlos, Schuster, Marc, Neumann, Yvonne, Heise, Ulrike, Pils, Marina C., Schulze-Osthoff, Klaus, Schmitz, Ingo
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Blocking - pharmacology; apoptosis; Autoimmunity - drug effects; c-FLIP; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; Caspase Inhibitors - pharmacology; Cell Death - drug effects; Cell Survival - drug effects; Cflar; Fas Ligand Protein - metabolism; fas Receptor - metabolism; Forkhead Transcription Factors - metabolism; Gene Deletion; Lymph Nodes - cytology; Mice; Phenotype; regulatory T cell; Spleen - cytology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.12.022

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. [Display omitted] •Treg cells exhibit a high rate of apoptosis ex vivo•Treg cells express lower levels of c-FLIPL than Tcon•Treg-specific deletion of Cflar/c-FLIP results in a scurfy-like phenotype•c-FLIP has additional functions in Treg cells than inhibition of CD95 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.