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Mina, an Il4 repressor, controls T helper type 2 bias

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Abstract

T helper type 2 (TH2) bias, which is the propensity of naive CD4+ T cells to differentiate into interleukin 4 (IL-4)-secreting TH2 cells, is a genetic trait that affects susceptibility to infectious, autoimmune and allergic diseases. TH2 bias correlates with the amount of IL-4 initially secreted by newly activated helper T cells that feeds back positively through the pathway of the IL-4 receptor and the transcription factors STAT6 and GATA-3 to drive TH2 development. Here we identify Mina, a member of the jumonji C (JmjC) protein family, as a genetic determinant of TH2 bias. Mina specifically bound to and repressed the Il4 promoter. Mina overexpression in transgenic mice impaired Il4 expression, whereas its knockdown in primary CD4+ T cells led to Il4 derepression. Our findings collectively provide mechanistic insight into an Il4-regulatory pathway that controls helper T cell differentiation and genetic variation in TH2 bias.

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Figure 1: Mina is a Dice1.2 candidate gene.
Figure 2: Inverse correlation of Mina and Il4 expression in naive helper T cells.
Figure 3: Mina is transcriptionally regulated.
Figure 4: Mina haplotype can be used to predict TH2-bias phenotype.
Figure 5: Mina can bind to and repress transcription from the Il4 promoter.
Figure 6: Recruitment of Mina to the Il4 promoter requires NFAT.
Figure 7: A transient enforced increase in Mina impairs Il4 expression in CD4+ T cells.
Figure 8: Il4 expression in CD4+ T cells is constrained by Mina-dependent repression.

Change history

  • 05 July 2009

    In the version of this article initially published online, the second corresponding author initials were incorrect. The correct initials are “M.Ku.” The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank R. Abe (Science University of Tokyo) for hybridoma PV-1; J. Allison (Memorial Sloan Kettering Cancer) for hybridoma 37N51.1; G. Trinchieri (US National Insitutes of Health) for hybridoma C17.8; A. Matsuno, M. Nakamura, M. Natsume, J. Epler, Y. Zhang, N. Li, S. Brown and R. Cross for technical help; J. Partridge for discussions; and D. Green, H. Beere and J. Kang (U. Mass. Medical School) for comments on the manuscript. Supported by the Cancer Research Institute (M.B.), the Burroughs Wellcome Fund (M.B.), American Lebanese Syrian Associated Charities (M.B.), the RIKEN Research Center for Allergy and Immunology International Collaboration Award Program (M.B. and M.Ku.), a Grant-in-Aid for Scientific Research (B) (M.Ku.), a Grant-in-Aid for Scientific Research on Priority Areas of the Ministry of Education, Culture, Sports, Science, and Technology (Japan) (M.Ku.), the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (M.Ku.) and the US National Institutes of Health (AI048636 to M.B.).

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Authors

Contributions

M.O. and M.V.S. did the experiments; L.C. did the Mina transcriptional analysis and Figures 2b and 3b and Supplementary Figure 2; M.Ka. did the Mina immunoblots; X.S. analyzed the C16D2/8D mice; Y.S. did the transgenic experiments; Y.S. and L.C. maintained the mouse colonies; O.O., H.K. and A.H. did the expression profiling; M.O., M.V.S., M.Ku and M.B. designed and conceptualized the research and analyzed the data; and M.B. prepared the manuscript.

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Correspondence to Masato Kubo or Mark Bix.

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Okamoto, M., Van Stry, M., Chung, L. et al. Mina, an Il4 repressor, controls T helper type 2 bias. Nat Immunol 10, 872–879 (2009). https://doi.org/10.1038/ni.1747

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