BACKGROUND CD4+ T cells play essential roles in adaptive immunity. Distinct CD4+ T cell subsets - Th1, Th2, Th17, Th22, T follicular helper and regulatory T cells - have been identified and their contributions to host defence and immune regulation are increasingly well-defined. IL-9 producing Th9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human Th9 cells remain incompletely defined. OBJECTIVE Define signalling pathways that regulate IL-9 production by human CD4+ T cells. METHODS Human naive and memory CD4+ T cells were cultured under different conditions and the molecular mechanisms regulating IL-9 induction were determined by assessing the ability of CD4+ T cells from a broad range of patients (n=92) with pathogenic variants in key immune genes (n=21) to differentiate into IL-9+ cells. RESULTS We identified two culture conditions that yielded IL-9-expressing cells from naïve CD4+ T cells, and amplified IL-9 production by in vivo-generated memory CD4+ T cells: TGFβ plus IL-4 (i.e. Th9 polarising condition), and the combination of IL-21, IL-23, IL-6, IL-1β and TGFβ (i.e. Th17 polarising condition). Combining these conditions had a synergistic effect in generating IL-9+CD4+ T cells. IL-9 induction required STAT3-activating cytokines as well as intact signalling via the TCR and STAT5. Importantly, IL-9 induction was restrained by IFNγ/STAT1 and IL-10. CONCLUSIONS Our findings revealed critical molecules involved in inducing/restraining IL-9 production by human CD4+ T cells, thereby identifying pathways that could be targeted to modulate IL-9 in health and disease.

中文翻译：

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免疫的先天性缺陷揭示了产生和维持人类 IL-9 表达细胞的分子需求。


背景 CD4+ T 细胞在适应性免疫中起着重要作用。已经确定了不同的 CD4+ T 细胞亚群 - Th1、Th2、Th17、Th22、滤泡辅助性 T 细胞和调节性 T 细胞 - 它们对宿主防御和免疫调节的贡献越来越明确。产生 IL-9 的 Th9 细胞于 2008 年首次被描述，似乎在人体免疫中起着保护和致病作用。然而，生成人 Th9 细胞的关键要求仍未完全明确。目的 定义调节人 CD4 + T 细胞产生 IL-9 的信号通路。方法 在不同条件下培养人类幼稚和记忆 CD4+ T 细胞，通过评估来自具有关键免疫基因致病性变异 （n=21） 的广泛患者 （n=92） 的 CD4+ T 细胞分化为 IL-9+ 细胞的能力，确定调节 IL-9 诱导的分子机制。结果我们确定了两种从初始 CD4+ T 细胞中产生表达 IL-9 的细胞的培养条件，并通过体内生成的记忆 CD4+ T 细胞扩增了 IL-9 的产生：TGFβ 加 IL-4（即 Th9 极化条件），以及 IL-21、IL-23、IL-6、IL-1β 和 TGFβ 的组合（即 Th17 极化条件）。结合这些条件在产生 IL-9 + CD4 + T 细胞方面具有协同作用。IL-9 诱导需要激活 STAT3 的细胞因子以及通过 TCR 和 STAT5 的完整信号传导。重要的是，IL-9 诱导受到 IFNγ/STAT1 和 IL-10 的抑制。结论 我们的研究结果揭示了参与诱导/抑制人类 CD4+ T 细胞产生 IL-9 的关键分子，从而确定了在健康和疾病中靶向调节 IL-9 的途径。