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

Authors

  • L. Gabryšová
  • M. Alvarez-Martinez
  • R. Luisier
  • L.S. Cox
  • J. Sodenkamp
  • C. Hosking
  • D. Pérez-Mazliah
  • C. Whicher
  • Y. Kannan
  • K. Potempa
  • X. Wu
  • L. Bhaw
  • H. Wende
  • M.H. Sieweke
  • G. Elgar
  • M. Wilson
  • J. Briscoe
  • V. Metzis
  • J. Langhorne
  • N.M. Luscombe
  • A. O'Garra

Journal

  • Nature Immunology

Citation

  • Nat Immunol 19 (5): 497-507

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 T(H)1 subset of helper T cells (malaria), T(H)2 cells (allergy) and T(H)17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in T(H)1 and T(H)2 responses, T(H)17 cell-mediated pathology was reduced in this context, with an accompanying decrease in T(H)17 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 ROR?t (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.


DOI

doi:10.1038/s41590-018-0083-5