Thymus-derived regulatory T cells are positively selected on natural self-antigen through cognate interactions of high functional avidity
2016
Kieback, Elisa | Hilgenberg, Ellen | Stervbo, Ulrik | Lampropoulou, Vicky | Shen, Ping | Bunse, Mario | Jaimes, Yarua | Boudinot, Pierre | Radbruch, Andreas | Klemm, Uwe | Kühl, Anja A. | Liblau, Roland | Hoevelmeyer, Nadine | Anderton, Stephen M. | Uckert, Wolfgang | Fillatreau, Simon | Institute of Biology ; Humboldt-Universität zu Berlin = Humboldt University of Berlin = Université Humboldt de Berlin (HU Berlin) | Max Delbrück Center for Molecular Medicine [Berlin] (MDC) ; Helmholtz-Gemeinschaft = Helmholtz Association | Leibniz Association | Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)) ; Institut National de la Recherche Agronomique (INRA) | Max Planck Institute for Infection Biology (MPIIB) ; Max-Planck-Gesellschaft | Institute of Pathology ; Charité - UniversitätsMedizin = Berlin University Medicine | Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT) | Institute for Molecular Medicine ; Institute for Molecular Medicine | The University of Edinburgh | Faculté de Médecine ; Université de Ngozi [Burundi] | Université Sorbonne Paris Cité (COMUE) (USPC) | Hôpital Necker - Enfants Malades [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) | Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)) ; Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) | Deutsche Forschungsgemeinschaft [SFB-TR-36, SFB-650]
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Show more [+] Less [-]English. 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.
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