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c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells

Research output: Contribution to journalArticle

Author(s)

  • Leona Gabryšová
  • Marisol Alvarez-Martinez
  • Raphaëlle Luisier
  • Luke S Cox
  • Jan Sodenkamp
  • Caroline Hosking
  • Charlotte Whicher
  • Yashaswini Kannan
  • Krzysztof Potempa
  • Xuemei Wu
  • Leena Bhaw
  • Hagen Wende
  • Michael H Sieweke
  • Greg Elgar
  • Mark Wilson
  • James Briscoe
  • Vicki Metzis
  • Jean Langhorne
  • Nicholas M Luscombe
  • Anne O'Garra

Department/unit(s)

Publication details

JournalNature immunology
DateAccepted/In press - 8 Mar 2018
DatePublished (current) - 1 May 2018
Issue number5
Volume19
Number of pages11
Pages (from-to)497-507
Original languageEnglish

Abstract

The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4+ T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4+ T cells in disease models involving the TH1 subset of helper T cells (malaria), TH2 cells (allergy) and TH17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in TH1 and TH2 responses, TH17 cell-mediated pathology was reduced in this context, with an accompanying decrease in TH17 cells and increase in Foxp3+ regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.

    Research areas

  • Animals, CD4-Positive T-Lymphocytes/immunology, Gene Expression Regulation/immunology, Gene Regulatory Networks/immunology, Interleukin-2/biosynthesis, Mice, Proto-Oncogene Proteins c-maf/immunology

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