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

Nat Immunol. 2018 May;19(5):497-507. doi: 10.1038/s41590-018-0083-5. Epub 2018 Apr 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Interleukin-2
  • Maf protein, mouse
  • Proto-Oncogene Proteins c-maf