Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, 20892, MD, USA.
Systemic Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 31 Center Drive, Bethesda, 20892, MD, USA.
Nat Commun. 2022 Oct 14;13(1):6069. doi: 10.1038/s41467-022-33733-8.
Interleukin-9 (IL-9)-producing CD4 T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation from activated T cells, driven by IL-4 and transforming growth factor-beta (TGF-β), is still lacking. Here we show opposing functions of two transcription factors, D-binding protein (DBP) and E2F8, in controlling Th9 differentiation. Specifically, TGF-β and IL-4 signaling induces phosphorylation of the serine 213 site in the linker region of the Smad3 (pSmad3L-Ser) via phosphorylated p38, which is necessary and sufficient for Il9 gene transcription. We identify DBP and E2F8 as an activator and repressor, respectively, for Il9 transcription by pSmad3L-Ser. Notably, Th9 cells with siRNA-mediated knockdown for Dbp or E2f8 promote and suppress tumor growth, respectively, in mouse tumor models. Importantly, DBP and E2F8 also exhibit opposing functions in regulating human TH9 differentiation in vitro. Thus, our data uncover a molecular mechanism of Smad3 linker region-mediated, opposing functions of DBP and E2F8 in Th9 differentiation.
白细胞介素-9（IL-9）产生的 CD4 T 辅助细胞（Th9）被认为与过敏/哮喘和抗肿瘤免疫有关，但对于它们如何从 IL-4 和转化生长因子-β（TGF-β）激活的 T 细胞分化而来，仍缺乏分子层面的认识。在这里，我们展示了两个转录因子 D 结合蛋白（DBP）和 E2F8 在控制 Th9 分化中的相反功能。具体来说，TGF-β 和 IL-4 信号通过磷酸化的 p38 诱导 Smad3 连接区丝氨酸 213 位点的磷酸化（pSmad3L-Ser），这对于 Il9 基因转录是必要和充分的。我们确定 DBP 和 E2F8 分别作为 Il9 转录的激活子和抑制剂，用于 pSmad3L-Ser。值得注意的是，用 siRNA 介导的 Dbp 或 E2f8 敲低的 Th9 细胞分别促进和抑制了小鼠肿瘤模型中的肿瘤生长。重要的是，DBP 和 E2F8 也在体外调节人类 TH9 分化中表现出相反的功能。因此，我们的数据揭示了 Smad3 连接区介导的、DBP 和 E2F8 在 Th9 分化中的相反功能的分子机制。
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