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The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-β and suppresses TH2 differentiation

Abstract

Sox4 is a transcription factor that regulates various developmental processes. Here we show that Sox4 was induced by TGF-β and negatively regulated the transcription factor GATA-3, the master regulator of function of T helper type 2 (TH2) cells, by two distinct mechanisms. First, Sox4 bound directly to GATA-3, preventing its binding to GATA-3 consensus DNA sequences. Second, Sox4 bound to the promoter region of the gene encoding interleukin 5 (IL-5), a TH2 cytokine, and prevented binding of GATA-3 to this promoter. TH2 cell–driven airway inflammation was modulated by alterations in Sox4 expression. Thus, Sox4 acted as a downstream target of TGF-β to inhibit GATA-3 function, TH2 differentiation and TH2 cell–mediated inflammation.

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Figure 1: TGF-β-induced Sox4 expression in CD4+ T cells.
Figure 2: Involvement of Sox4 in the TGF-β-mediated inhibition of TH2 differentiation.
Figure 3: Enforced expression of Sox4 inhibits TH2 differentiation.
Figure 4: Physical association of Sox4 with GATA-3.
Figure 5: Sox4 interferes with the binding of GATA-3 to DNA.
Figure 6: Attenuated OVA-induced allergic airway inflammation in Sox4-transgenic mice.
Figure 7: Enhanced OVA-induced allergic airway inflammation in mice with CD4+ T cell–specific Sox4 deficiency.

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Acknowledgements

We thank D. Loh (Washington University School of Medicine) for DO11.10 mice; R. Kubo, A. Singer and D. Singer for comments and criticisms in the preparation of this manuscript; and K. Sugaya, H. Asou, S. Norikane, M. Kato and T. Ito for technical assistance. Supported by the Global Center for Education and Research in Immune System Regulation and Treatment, City Area Program (Kazusa/Chiba Area) of the Ministry of Education, Culture, Sports, Science and Technology of Japan, Japan Science and Technology Agency Core Research for Evolutional Science and Technology, Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology, the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grants-in-Aid for Scientific Research on Priority Areas 22021008 and 22021011; Scientific Research (B) 21390147 and 23390075), the Ministry of Health, Labor and Welfare of Japan, the Uehara Memorial Foundation, the Mochida Foundation, the Naito Foundation and the Takeda Science Foundation.

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M.K. and M.Y. designed and did experiments, analyzed data and wrote the manuscript; K.S., S.T., A.O., R.S., S.M., D.T., H.H. and C.I. designed and did experiments and edited the manuscript; V.L. established Sox4 deficient mice; and T.N. conceptualized the research, directed the study and wrote and edited the manuscript.

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Correspondence to Toshinori Nakayama.

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Kuwahara, M., Yamashita, M., Shinoda, K. et al. The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-β and suppresses TH2 differentiation. Nat Immunol 13, 778–786 (2012). https://doi.org/10.1038/ni.2362

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