title: Thymus-Derived Regulatory T Cells Are Positively Selected on Natural Self-Antigen through Cognate Interactions of High Functional Avidity.
abstract: Regulatory T (Treg) cells expressing Foxp3 transcripton factor are essential for immune homeostasis. They arise in the thymus as a separate lineage from conventional CD4(+)Foxp3(-) T (Tconv) cells. Here, we show that the thymic development of Treg cells depends on the expression of their endogenous cognate self-antigen. The formation of these cells was impaired in mice lacking this self-antigen, while Tconv cell development was not negatively affected. Thymus-derived Treg cells were selected by self-antigens in a specific manner, while autoreactive Tconv cells were produced through degenerate recognition of distinct antigens. These distinct modes of development were associated with the expression of T cell receptor of higher functional avidity for self-antigen by Treg cells than Tconv cells, a difference subsequently essential for the control of autoimmunity. Our study documents how self-antigens define the repertoire of thymus-derived Treg cells to subsequently endow this cell type with the capacity to undermine autoimmune attack.
authors.affiliation: Humboldt University of Berlin, Institute of Biology, 10115 Berlin, Germany; Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Kieback
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Hilgenberg
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Stervbo
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Vicky
authors.initials: V
authors.lastname: Lampropoulou
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Ping
authors.initials: P
authors.lastname: Shen
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Bunse
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Yarua
authors.initials: Y
authors.lastname: Jaimes
authors.affiliation: INRA, Unité de Virologie et Immunologie Moléculaire, 78352 Jouy en Josas, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Boudinot
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.affiliation: Max Planck Institute of Infection Biology, 10117 Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Klemm
authors.affiliation: Institute of Pathology/RCIS, Charité, Campus Benjamin Franklin, 12203 Berlin, Germany.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: CPTP, INSERM UMR 1043 / CNRS UMR 5282, Université Toulouse III, 31024 Toulouse, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Liblau
authors.affiliation: Institute for Molecular Medicine, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hoevelmeyer
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, The Queens Medical Research Institute, Edinburgh, EH16 4TJ, UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
authors.affiliation: Humboldt University of Berlin, Institute of Biology, 10115 Berlin, Germany; Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uckert
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany; Institut Necker-Enfants Malades (INEM), INSERM U1151-CNRS UMR 8253, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants Malades, Paris, France. Electronic address: simon.fillatreau@inserm.fr.
authors.forename: Simon
authors.initials: S
authors.lastname: Fillatreau
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D060966:Clonal Selection, Antigen-Mediated; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology*
chemical_list: D001324:Autoantigens; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C445081:myelin oligodendrocyte glycoprotein (35-55)