Continuous T cell receptor signals maintain a functional regulatory T cell pool

J Christoph Vahl; Christoph Drees; Klaus Heger; Sylvia Heink; Julius C Fischer; Jelena Nedjic; Naganari Ohkura; Hiromasa Morikawa; Hendrik Poeck; Sonja Schallenberg; David Rieß; Marco Y Hein; Thorsten Buch; Bojan Polic; Anne Schönle; Robert Zeiser; Annette Schmitt-Gräff; Karsten Kretschmer; Ludger Klein; Thomas Korn; Shimon Sakaguchi; Marc Schmidt-Supprian

doi:10.1016/j.immuni.2014.10.012

Continuous T cell receptor signals maintain a functional regulatory T cell pool

Immunity. 2014 Nov 20;41(5):722-36. doi: 10.1016/j.immuni.2014.10.012. Epub 2014 Nov 6.

Authors

J Christoph Vahl¹, Christoph Drees², Klaus Heger³, Sylvia Heink⁴, Julius C Fischer², Jelena Nedjic⁵, Naganari Ohkura⁶, Hiromasa Morikawa⁶, Hendrik Poeck², Sonja Schallenberg⁷, David Rieß³, Marco Y Hein¹, Thorsten Buch⁸, Bojan Polic⁹, Anne Schönle¹⁰, Robert Zeiser¹⁰, Annette Schmitt-Gräff¹¹, Karsten Kretschmer⁷, Ludger Klein⁵, Thomas Korn⁴, Shimon Sakaguchi⁶, Marc Schmidt-Supprian¹²

Affiliations

¹ Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
² Department of Hematology, Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 15, 81675 Munich, Germany.
³ 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.
⁴ Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 15, 81675 Munich, Germany.
⁵ Institute for Immunology, Ludwig-Maximilians University, Goethestraße 31, 80336 Munich, Germany.
⁶ Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
⁷ Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
⁸ 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.
⁹ University of Rijeka School of Medicine, B. Branchetta 20, HR-51000 Rijeka, Croatia.
¹⁰ Department of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany.
¹¹ Department of Pathology, University Hospital Freiburg, Breisacher Straße 115a, 79106 Freiburg Germany.
¹² 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.

PMID: 25464853
DOI: 10.1016/j.immuni.2014.10.012

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.

MeSH terms

Animals
Autoimmunity / immunology*
Cell Differentiation / immunology
Cell Lineage / immunology
DNA Methylation / immunology
DNA-Binding Proteins / genetics
Forkhead Transcription Factors / biosynthesis*
Forkhead Transcription Factors / genetics
Inflammation / immunology
Interferon Regulatory Factors / biosynthesis
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Mice
Mice, Inbred C57BL
Mice, Knockout
Multiprotein Complexes / metabolism
Receptors, Antigen, T-Cell, alpha-beta / genetics
Receptors, Antigen, T-Cell, alpha-beta / immunology*
Signal Transduction / immunology
T-Lymphocytes, Regulatory / immunology*
TOR Serine-Threonine Kinases / metabolism
Thymocytes / cytology

Substances

DNA-Binding Proteins
Forkhead Transcription Factors
Foxp3 protein, mouse
Interferon Regulatory Factors
Multiprotein Complexes
Rag2 protein, mouse
Receptors, Antigen, T-Cell, alpha-beta
interferon regulatory factor-4
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
TOR Serine-Threonine Kinases

Associated data

GEO/GSE62532