The DNA-binding inhibitor Id3 regulates IL-9 production in CD4(+) T cells

  • Nat Immunol. 2015 Oct;16(10):1077-84. doi: 10.1038/ni.3252.
Hiroko Nakatsukasa  1 ,  Dunfang Zhang  1  2 ,  Takashi Maruyama  1 ,  Hua Chen  1 ,  Kairong Cui  3 ,  Masaki Ishikawa  4 ,  Lisa Deng  1 ,  Peter Zanvit  1 ,  Eric Tu  1 ,  Wenwen Jin  1 ,  Brittany Abbatiello  1 ,  Nathan Goldberg  1 ,  Qianming Chen  2 ,  Lingyun Sun  5 ,  Keji Zhao  3 ,  WanJun Chen  1
Affiliations
  • 1. Mucosal Immunology Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
  • 2. State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • 3. Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • 4. Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
  • 5. Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
PMID: 26322481 DOI: 10.1038/ni.3252
Abstract

The molecular mechanisms by which signaling via transforming growth factor-β (TGF-β) and interleukin 4 (IL-4) control the differentiation of CD4(+) IL-9-producing helper T cells (TH9 cells) remain incompletely understood. We found here that the DNA-binding inhibitor Id3 regulated TH9 differentiation, as deletion of Id3 increased IL-9 production from CD4(+) T cells. Mechanistically, TGF-β1 and IL-4 downregulated Id3 expression, and this process required the kinase TAK1. A reduction in Id3 expression enhanced binding of the Transcription Factors E2A and GATA-3 to the Il9 promoter region, which promoted Il9 transcription. Notably, Id3-mediated control of TH9 differentiation regulated anti-tumor immunity in an experimental melanoma-bearing model in vivo and also in human CD4(+) T cells in vitro. Thus, our study reveals a previously unrecognized TAK1-Id3-E2A-GATA-3 pathway that regulates TH9 differentiation.

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