Science and Research

Reciprocal regulation of the Il9 locus by counteracting activities of transcription factors IRF1 and IRF4

The T helper 9 (Th9) cell transcriptional network is formed by an equilibrium of signals induced by cytokines and antigen presentation. Here we show that, within this network, two interferon regulatory factors (IRF), IRF1 and IRF4, display opposing effects on Th9 differentiation. IRF4 dose-dependently promotes, whereas IRF1 inhibits, IL-9 production. Likewise, IRF1 inhibits IL-9 production by human Th9 cells. IRF1 counteracts IRF4-driven Il9 promoter activity, and IRF1 and IRF4 have opposing function on activating histone modifications, thus modulating RNA polymerase II recruitment. IRF1 occupancy correlates with decreased IRF4 abundance, suggesting an IRF1-IRF4-binding competition at the Il9 locus. Furthermore, IRF1 shapes Th9 cells with an interferon/Th1 gene signature. Consistently, IRF1 restricts the IL-9-dependent pathogenicity of Th9 cells in a mouse model of allergic asthma. Thus our study reveals that the molecular ratio between IRF4 and IRF1 balances Th9 fate, thus providing new possibilities for manipulation of Th9 differentiation.

  • Campos Carrascosa, L.
  • Klein, M.
  • Kitagawa, Y.
  • Luckel, C.
  • Marini, F.
  • Konig, A.
  • Guralnik, A.
  • Raifer, H.
  • Hagner-Benes, S.
  • Radler, D.
  • Bock, A.
  • Kang, C.
  • Lohoff, M.
  • Garn, H.
  • Schaub, B.
  • Berberich-Siebelt, F.
  • Sakaguchi, S.
  • Bopp, T.
  • Huber, M.

Keywords

  • Animals
  • CD4-Positive T-Lymphocytes/cytology/metabolism
  • Cell Differentiation/genetics
  • Gene Expression Profiling
  • Humans
  • Interferon Regulatory Factor-1/genetics/*metabolism
  • Interferon Regulatory Factors/genetics/*metabolism
  • Interleukin-9/genetics/*metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • T-Lymphocytes, Helper-Inducer/cytology/*metabolism
Publication details
DOI: 10.1038/ncomms15366
Journal: Nature communications
Pages: 15366 
Work Type: Original
Location: CPC-M, UGMLC
Disease Area: General Lung and Other
Partner / Member: LMU, UMR
Access-Number: 28497800
See publication on PubMed

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