A20 Restrains Thymic Regulatory T Cell Development

Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (T-reg) cells in the thymus. Activation of NF-kappa B transcription factors is critically required for T-reg cell development, partly via initiating Foxp3 expression. NF-kB 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-kappa B transcription factor Re1A 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 Treg 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.