A20 Restrains Thymic Regulatory T Cell Development

Medientyp: E-Artikel

Titel: A20 Restrains Thymic Regulatory T Cell Development

Beteiligte: Fischer, Julius Clemens; Otten, Vera; Kober, Maike; Drees, Christoph; Rosenbaum, Marc; Schmickl, Martina; Heidegger, Simon; Beyaert, Rudi; van Loo, Geert; Li, Xian Chang; Peschel, Christian; Schmidt-Supprian, Marc; Haas, Tobias; Spoerl, Silvia; Poeck, Hendrik

Erschienen: The American Association of Immunologists, 2017

Sprache: Englisch

DOI: 10.4049/jimmunol.1602102

ISSN: 0022-1767; 1550-6606

Schlagwörter: Immunology ; Immunology and Allergy

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Beschreibung: Abstract Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (Treg) cells in the thymus. Activation of NF-κB transcription factors is critically required for Treg 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 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-κB 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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