The transcription factor c-Maf is essential for the commitment of IL-17-producing γδ T cells

Nat Immunol. 2019 Jan;20(1):73-85. doi: 10.1038/s41590-018-0274-0. Epub 2018 Dec 10.

Abstract

γδ T cells that produce the cytokine IL-17 (Tγδ17 cells) are innate-like mediators of immunity that undergo effector programming in the thymus. While regulators of Tγδ17 specialization restricted to various Vγ subsets are known, a commitment factor essential to all Tγδ17 cells has remained undefined. In this study, we identified the transcription factor c-Maf as a universal regulator of Tγδ17 cell differentiation and maintenance. Maf deficiency caused an absolute lineage block at the immature CD24+CD45RBlo γδ thymocyte stage, which revealed a critical checkpoint in the acquisition of effector functions. Here, c-Maf enforced Tγδ17 cell identity by promoting chromatin accessibility and expression of key type 17 program genes, notably Rorc and Blk, while antagonizing the transcription factor TCF1, which promotes interferon-γ-producing γδ T cells (Tγδ1 cells). Furthermore, γδ T cell antigen receptor (γδTCR) signal strength tuned c-Maf expression, which indicates that c-Maf is a core node that connects γδTCR signals to Tγδ17 cell transcriptional programming.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD24 Antigen / metabolism
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Cells, Cultured
  • Immunity, Innate
  • Interleukin-17 / metabolism*
  • Leukocyte Common Antigens / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Proto-Oncogene Proteins c-maf / genetics
  • Proto-Oncogene Proteins c-maf / metabolism*
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Signal Transduction
  • Th17 Cells / physiology*
  • Thymocytes / physiology*
  • src-Family Kinases / genetics

Substances

  • CD24 Antigen
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Proto-Oncogene Proteins c-maf
  • Receptors, Antigen, T-Cell, gamma-delta
  • Rorc protein, mouse
  • B lymphoid kinase, mouse
  • src-Family Kinases
  • Leukocyte Common Antigens