T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt

Nat Immunol. 2011 Jan;12(1):96-104. doi: 10.1038/ni.1969. Epub 2010 Dec 12.

Abstract

Overactive responses by interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) are tightly linked to the development of autoimmunity, yet the factors that negatively regulate the differentiation of this lineage remain unknown. Here we report that the transcription factor T-bet suppressed development of the T(H)17 cell lineage by inhibiting transcription of Rorc (which encodes the transcription factor RORγt). T-bet interacted with the transcription factor Runx1, and this interaction blocked Runx1-mediated transactivation of Rorc. T-bet Tyr304 was required for formation of the T-bet-Runx1 complex, for blockade of Runx1 activity and for inhibition of the T(H)17 differentiation program. Our data reinforce the idea of master regulators that shape immune responses by simultaneously activating one genetic program while silencing the activity of competing regulators in a common progenitor cell.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Cells, Cultured
  • Core Binding Factor Alpha 2 Subunit / immunology
  • Core Binding Factor Alpha 2 Subunit / metabolism*
  • Cytokines / genetics
  • Cytokines / immunology
  • Cytokines / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
  • Protein Binding / genetics
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology
  • T-Box Domain Proteins / metabolism*
  • Th17 Cells / immunology
  • Th17 Cells / metabolism*
  • Th17 Cells / pathology

Substances

  • Core Binding Factor Alpha 2 Subunit
  • Cytokines
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • T-Box Domain Proteins
  • T-box transcription factor TBX21