A Network of High-Mobility Group Box Transcription Factors Programs Innate interleukin-17 Production

Immunity. 2013 Apr 18;38(4):681-93. doi: 10.1016/j.immuni.2013.01.010. Epub 2013 Apr 4.

Abstract

How innate lymphoid cells (ILCs) in the thymus and gut become specialized effectors is unclear. The prototypic innate-like γδ T cells (Tγδ17) are a major source of interleukin-17 (IL-17). We demonstrate that Tγδ17 cells are programmed by a gene regulatory network consisting of a quartet of high-mobility group (HMG) box transcription factors, SOX4, SOX13, TCF1, and LEF1, and not by conventional TCR signaling. SOX4 and SOX13 directly regulated the two requisite Tγδ17 cell-specific genes, Rorc and Blk, whereas TCF1 and LEF1 countered the SOX proteins and induced genes of alternate effector subsets. The T cell lineage specification factor TCF1 was also indispensable for the generation of IL-22 producing gut NKp46(+) ILCs and restrained cytokine production by lymphoid tissue inducer-like effectors. These results indicate that similar gene network architecture programs innate sources of IL-17, independent of anatomical origins.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • Autoantigens / genetics
  • Autoantigens / metabolism
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Gene Regulatory Networks / immunology
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • High Mobility Group Proteins / genetics
  • High Mobility Group Proteins / metabolism*
  • Immunity, Innate / genetics
  • Interleukin-17 / biosynthesis*
  • Interleukin-17 / genetics
  • Interleukins / immunology
  • Intestines / immunology*
  • Lymphocyte Subsets / immunology*
  • Lymphoid Enhancer-Binding Factor 1 / genetics
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Natural Cytotoxicity Triggering Receptor 1 / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • SOXC Transcription Factors / genetics
  • SOXC Transcription Factors / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*
  • Transcriptional Activation / immunology

Substances

  • Antigens, Ly
  • Autoantigens
  • Hepatocyte Nuclear Factor 1-alpha
  • High Mobility Group Proteins
  • Hnf1a protein, mouse
  • Interleukin-17
  • Interleukins
  • Lef1 protein, mouse
  • Lymphoid Enhancer-Binding Factor 1
  • Natural Cytotoxicity Triggering Receptor 1
  • Ncr1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Antigen, T-Cell, gamma-delta
  • SOXC Transcription Factors
  • Sox13 protein, mouse
  • Sox4 protein, mouse
  • interleukin-22