A20 Restrains Thymic Regulatory T Cell Development #MMPMID28842469
Fischer JC; Otten V; Kober M; Drees C; Rosenbaum M; Schmickl M; Heidegger S; Beyaert R; van Loo G; Li XC; Peschel C; Schmidt-Supprian M; Haas T; Spoerl S; Poeck H
J Immunol 2017[Oct]; 199 (7): 2356-65 PMID28842469show ga
Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (Treg) cells in the thymus. Activation of NF-?B transcription factors is critically required for Treg cell development, partly via initiating Foxp3 expression. NF-?B 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 Treg cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic Treg differentiation. A20-deficient thymic Treg cells exhibit reduced dependence on IL-2 but unchanged rates of proliferation and apoptosis. Activation of the NF-?B transcription factor RelA was enhanced, whereas nuclear translocation of c-Rel was decreased in A20-deficient thymic Treg cells. Furthermore, we found that the increase in Treg cells in T cell?specific A20-deficient mice was already observed in CD4+ single-positive CD25+ GITR+ Foxp3? thymic Treg cell progenitors. Treg cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic Treg cell development. A20-deficient Treg 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 Treg cells in check, A20 thus integrates Treg cell activity and increased effector T cell survival into an efficient CD4+ T cell response.
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J+Immunol 2017 ; 199 (7): 2356-65
