title: c-FLIP Expression in Foxp3-Expressing Cells Is Essential for Survival of Regulatory T Cells and Prevention of Autoimmunity.
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.
authors.affiliation: Systems-Oriented Immunology and Inflammation Research Group, Department of Immune Control, Helmholtz Center for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany; Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Straße 44, 39120 Magdeburg, Germany.
authors.forename: Carlos
authors.initials: C
authors.lastname: Plaza-Sirvent
authors.affiliation: Systems-Oriented Immunology and Inflammation Research Group, Department of Immune Control, Helmholtz Center for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany; Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Straße 44, 39120 Magdeburg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schuster
authors.affiliation: Systems-Oriented Immunology and Inflammation Research Group, Department of Immune Control, Helmholtz Center for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany; Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Straße 44, 39120 Magdeburg, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Neumann
authors.affiliation: Mouse Pathology Platform, Helmholtz Center for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Heise
authors.affiliation: Mouse Pathology Platform, Helmholtz Center for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany.
authors.forename: Marina C
authors.initials: MC
authors.lastname: Pils
authors.affiliation: Interfaculty Institute for Biochemistry, University of Tübingen, Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.affiliation: Systems-Oriented Immunology and Inflammation Research Group, Department of Immune Control, Helmholtz Center for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany; Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Straße 44, 39120 Magdeburg, Germany. Electronic address: ingo.schmitz@helmholtz-hzi.de.
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmitz
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015551:Autoimmunity / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D017353:Gene Deletion; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D010641:Phenotype; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D061945:Caspase Inhibitors; C506387:Cflar protein, mouse; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019014:fas Receptor
keywords: Cflar; apoptosis; c-FLIP; regulatory T cell