A20 Restrains Thymic Regulatory T Cell Development

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

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2356-2365
Number of pages10
JournalJournal of Immunology
Volume199
Issue number7
DOIs
StatePublished - Oct 1 2017

Keywords

  • Animals
  • Apoptosis
  • CD4-Positive T-Lymphocytes
  • Cell Differentiation
  • Flow Cytometry
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Glucocorticoid-Induced TNFR-Related Protein
  • Graft vs Host Disease
  • Interleukin-2
  • Lymphocyte Activation
  • Mice
  • NF-kappa B
  • Proto-Oncogene Proteins c-rel
  • Signal Transduction
  • Stem Cell Transplantation
  • T-Lymphocytes, Regulatory
  • Thymus Gland
  • Transcription Factor RelA
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Journal Article
  • Research Support, Non-U.S. Gov't

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