title: Suppression of lethal autoimmunity by regulatory T cells with a single TCR specificity.
abstract: The regulatory T cell (T reg cell) T cell receptor (TCR) repertoire is highly diverse and skewed toward recognition of self-antigens. TCR expression by T reg cells is continuously required for maintenance of immune tolerance and for a major part of their characteristic gene expression signature; however, it remains unknown to what degree diverse TCR-mediated interactions with cognate self-antigens are required for these processes. In this study, by experimentally switching the T reg cell TCR repertoire to a single T reg cell TCR, we demonstrate that T reg cell function and gene expression can be partially uncoupled from TCR diversity. An induced switch of the T reg cell TCR repertoire to a random repertoire also preserved, albeit to a limited degree, the ability to suppress lymphadenopathy and T helper cell type 2 activation. At the same time, these perturbations of the T reg cell TCR repertoire led to marked immune cell activation, tissue inflammation, and an ultimately severe autoimmunity, indicating the importance of diversity and specificity for optimal T reg cell function.
authors.affiliation: Howard Hughes Medical Institute, Immunology Program, Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Andrew G
authors.identifier: 0000-0003-3717-7558
authors.initials: AG
authors.lastname: Levine
authors.affiliation: Howard Hughes Medical Institute, Immunology Program, Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Saskia
authors.initials: S
authors.lastname: Hemmers
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Antonio P
authors.identifier: 0000-0001-8182-8982
authors.initials: AP
authors.lastname: Baptista
authors.affiliation: Howard Hughes Medical Institute, Immunology Program, Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Michail
authors.initials: M
authors.lastname: Schizas
authors.affiliation: Howard Hughes Medical Institute, Immunology Program, Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Mehlika B
authors.initials: MB
authors.lastname: Faire
authors.affiliation: Howard Hughes Medical Institute, Immunology Program, Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Bruno
authors.identifier: 0000-0002-9150-863X
authors.initials: B
authors.lastname: Moltedo
authors.affiliation: Howard Hughes Medical Institute, Immunology Program, Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Catherine
authors.initials: C
authors.lastname: Konopacki
authors.affiliation: Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 80333 Munich, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Germain
authors.affiliation: Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA 98195.
authors.forename: Piper M
authors.identifier: 0000-0002-1812-1519
authors.initials: PM
authors.lastname: Treuting
authors.affiliation: Howard Hughes Medical Institute, Immunology Program, Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 rudenska@mskcc.org.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
mesh_terms: D000818:Animals; D015551:Autoimmunity; D051858:Forkhead Transcription Factors / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell