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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.Autoreactive Treg cells express TCR of higher functional avidity than Tconv cellsExpression of endogenous MOG controls the development of MOG-reactive Treg cellsThe avidity of their TCR controls the protective value of autoreactive Treg cellsTreg cells use CTLA-4 to limit autoimmune disease of the central nervous systemAutoreactive Treg cells are essential for limiting immunopathology. Fillatreau and colleagues demonstrate that the thymic development of these cells depends on the expression of endogenous self-antigens and TCR interactions of high functional avidity. TCR of high functional avidity are essential for the capacity of Treg cells to suppress autoimmunity.