title: Continuous T cell receptor signals maintain a functional regulatory T cell pool.
abstract: Regulatory T (Treg) cells maintain immune homeostasis and prevent inflammatory and autoimmune responses. During development, thymocytes bearing a moderately self-reactive T cell receptor (TCR) can be selected to become Treg cells. Several observations suggest that also in the periphery mature Treg cells continuously receive self-reactive TCR signals. However, the importance of this inherent autoreactivity for Treg cell biology remains poorly defined. To address this open question, we genetically ablated the TCR of mature Treg cells in vivo. These experiments revealed that TCR-induced Treg lineage-defining Foxp3 expression and gene hypomethylation were uncoupled from TCR input in mature Treg cells. However, Treg cell homeostasis, cell-type-specific gene expression and suppressive function critically depend on continuous triggering of their TCR.
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: J Christoph
authors.initials: JC
authors.lastname: Vahl
authors.affiliation: Department of Hematology, Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 15, 81675 Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Drees
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany; Department of Hematology, Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 15, 81675 Munich, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Heger
authors.affiliation: Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 15, 81675 Munich, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heink
authors.affiliation: Department of Hematology, Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 15, 81675 Munich, Germany.
authors.forename: Julius C
authors.initials: JC
authors.lastname: Fischer
authors.affiliation: Institute for Immunology, Ludwig-Maximilians University, Goethestraße 31, 80336 Munich, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Nedjic
authors.affiliation: Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
authors.forename: Naganari
authors.initials: N
authors.lastname: Ohkura
authors.affiliation: Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Morikawa
authors.affiliation: Department of Hematology, Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 15, 81675 Munich, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Poeck
authors.affiliation: Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schallenberg
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany; Department of Hematology, Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 15, 81675 Munich, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Rieß
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Marco Y
authors.initials: MY
authors.lastname: Hein
authors.affiliation: Institute for Medical Microbiology, Immunology & Hygiene, Trogerstraße 30, Technische Universität München, 81675 Munich, Germany and Institute of Laboratory Animal Sciences, University of Zurich, Winterthurer Straße 190, 8057 Zurich, Switzerland.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Buch
authors.affiliation: University of Rijeka School of Medicine, B. Branchetta 20, HR-51000 Rijeka, Croatia.
authors.forename: Bojan
authors.initials: B
authors.lastname: Polic
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schönle
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
authors.affiliation: Department of Pathology, University Hospital Freiburg, Breisacher Straße 115a, 79106 Freiburg Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Gräff
authors.affiliation: Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Kretschmer
authors.affiliation: Institute for Immunology, Ludwig-Maximilians University, Goethestraße 31, 80336 Munich, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein
authors.affiliation: Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 15, 81675 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Korn
authors.affiliation: Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany; Department of Hematology, Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 15, 81675 Munich, Germany. Electronic address: supprian@lrz.tum.de.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D019175:DNA Methylation / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D007249:Inflammation / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000096:biosynthesis; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology; D000099218:Interferon Regulatory Factor-4
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D050835:Interferon Regulatory Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D016693:Receptors, Antigen, T-Cell, alpha-beta; D058570:TOR Serine-Threonine Kinases; D000099218:Interferon Regulatory Factor-4; C498833:Foxp3 protein, mouse; C499308:Rag2 protein, mouse