1. c-FLIP Expression in Foxp3-Expressing Cells Is Essential for Survival of Regulatory T Cells and Prevention of Autoimmunity.
- Author
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Plaza-Sirvent C, Schuster M, Neumann Y, Heise U, Pils MC, Schulze-Osthoff K, and Schmitz I
- Subjects
- Animals, Antibodies, Blocking pharmacology, Caspase Inhibitors pharmacology, Cell Death drug effects, Cell Survival drug effects, Fas Ligand Protein metabolism, Gene Deletion, Lymph Nodes cytology, Mice, Phenotype, Spleen cytology, T-Lymphocytes, Regulatory drug effects, fas Receptor metabolism, Autoimmunity drug effects, CASP8 and FADD-Like Apoptosis Regulating Protein metabolism, Forkhead Transcription Factors metabolism, T-Lymphocytes, Regulatory immunology
- Abstract
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., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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