TY - JOUR
T1 - The DNA-binding inhibitor Id3 regulates IL-9 production in CD4 + T cells
AU - Nakatsukasa, Hiroko
AU - Zhang, Dunfang
AU - Maruyama, Takashi
AU - Chen, Hua
AU - Cui, Kairong
AU - Ishikawa, Masaki
AU - Deng, Lisa
AU - Zanvit, Peter
AU - Tu, Eric
AU - Jin, Wenwen
AU - Abbatiello, Brittany
AU - Goldberg, Nathan
AU - Chen, Qianming
AU - Sun, Lingyun
AU - Zhao, Keji
AU - Chen, Wanjun
N1 - Funding Information:
We thank J.E. Konkel and C. Chia for critical reading of the manuscript; Y. Zhuang (Duke University) for Id3f/fCd4-Cre+ mice; X.C. Li (Harvard Medical School) for antigen-presenting cells with transgenic expression of the ligand for OX40; Y. Wan (University of North Carolina) for Tak1f/fER-Cre mice; and A. Yoshimura (Keio University of Medicine) for Smad2f/fLck-Cre+ mice. Supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research (US National Institutes of Health) and the JSPS Research Fellowship Program for Japanese Biomedical and Behavioral Researchers at the US National Institutes of Health (H.N).
Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/9/18
Y1 - 2015/9/18
N2 - 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 (T H 9 cells) remain incompletely understood. We found here that the DNA-binding inhibitor Id3 regulated T H9 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 T H9 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 T H 9 differentiation.
AB - 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 (T H 9 cells) remain incompletely understood. We found here that the DNA-binding inhibitor Id3 regulated T H9 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 T H9 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 T H 9 differentiation.
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U2 - 10.1038/ni.3252
DO - 10.1038/ni.3252
M3 - Article
C2 - 26322481
AN - SCOPUS:84941996879
SN - 1529-2908
VL - 16
SP - 1077
EP - 1084
JO - Nature Immunology
JF - Nature Immunology
IS - 10
ER -