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Immunity. 2016 May 17;44(5):1114-26. doi: 10.1016/j.immuni.2016.04.018.

Thymus-Derived Regulatory T Cells Are Positively Selected on Natural Self-Antigen through Cognate Interactions of High Functional Avidity.

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Humboldt University of Berlin, Institute of Biology, 10115 Berlin, Germany; Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany.
Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
INRA, Unité de Virologie et Immunologie Moléculaire, 78352 Jouy en Josas, France.
Max Planck Institute of Infection Biology, 10117 Berlin, Germany.
Institute of Pathology/RCIS, Charité, Campus Benjamin Franklin, 12203 Berlin, Germany.
CPTP, INSERM UMR 1043 / CNRS UMR 5282, Université Toulouse III, 31024 Toulouse, France.
Institute for Molecular Medicine, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany.
MRC Centre for Inflammation Research, University of Edinburgh, The Queens Medical Research Institute, Edinburgh, EH16 4TJ, UK.
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:


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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