Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (T_reg) cells in the thymus. Activation of NF-κB transcription factors is critically required for T_reg cell development, partly via initiating Foxp3 expression. NF-κB activation is controlled by a negative feedback regulation through the ubiquitin editing enzyme A20, which reduces proinflammatory signaling in myeloid cells and B cells. In naive CD4⁺ T cells, A20 prevents kinase RIPK3-dependent necroptosis. Using mice deficient for A20 in T lineage cells, we show that thymic and peripheral T_reg cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic T_reg differentiation. A20-deficient thymic T_reg cells exhibit reduced dependence on IL-2 but unchanged rates of proliferation and apoptosis. Activation of the NF-κB transcription factor RelA was enhanced, whereas nuclear translocation of c-Rel was decreased in A20-deficient thymic T_reg cells. Furthermore, we found that the increase in T_reg cells in T cell-specific A20-deficient mice was already observed in CD4⁺ single-positive CD25⁺ GITR⁺ Foxp3^- thymic T_reg cell progenitors. T_reg cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic T_reg cell development. A20-deficient T_reg cells efficiently suppressed effector T cell-mediated graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, suggesting normal suppressive function. Holding thymic production of natural T_reg cells in check, A20 thus integrates T_reg cell activity and increased effector T cell survival into an efficient CD4⁺ T cell response.

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