Details

Autor(en) / 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

Titel

A20 Restrains Thymic Regulatory T Cell Development

Ist Teil von

• The Journal of immunology (1950), 2017-10, Vol.199 (7), p.2356-2365

Ort / Verlag

United States: American Association of Immunologists

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (T ) cells in the thymus. Activation of NF-κB transcription factors is critically required for T 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 cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic T differentiation. A20-deficient thymic T 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 cells. Furthermore, we found that the increase in T cells in T cell-specific A20-deficient mice was already observed in CD4 single-positive CD25 GITR Foxp3 thymic T cell progenitors. T cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic T cell development. A20-deficient T 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 cells in check, A20 thus integrates T cell activity and increased effector T cell survival into an efficient CD4 T cell response.