T helper (Th) 17 cells encompass a spectrum of cell states, including cells that maintain homeostatic tissue functions and pro-inflammatory cells that can drive autoimmune tissue damage. Identifying regulators that determine Th17 cell states can identify ways to control tissue inflammation and restore homeostasis. Here, we found that interleukin (IL)-23, a cytokine critical for inducing pro-inflammatory Th17 cells, decreased transcription factor T cell factor 1 (TCF1) expression. Conditional deletion of TCF1 in mature T cells increased the pro-inflammatory potential of Th17 cells, even in the absence of IL-23 receptor signaling, and conferred pro-inflammatory potential to homeostatic Th17 cells. Conversely, sustained TCF1 expression decreased pro-inflammatory Th17 potential. Mechanistically, TCF1 bound to RORγt, thereby interfering with its pro-inflammatory functions, and orchestrated a regulatory network that determined Th17 cell state. Our findings identify TCF1 as a major determinant of Th17 cell state and provide important insight for the development of therapies for Th17-driven inflammatory diseases.

中文翻译：

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转录因子 TCF1 与 RORγt 结合并协调确定稳态 Th17 细胞状态的调节网络


辅助性 T 细胞 （Th） 17 细胞包含一系列细胞状态，包括维持稳态组织功能的细胞和可驱动自身免疫组织损伤的促炎细胞。鉴定决定 Th17 细胞状态的调节因子可以确定控制组织炎症和恢复体内平衡的方法。在这里，我们发现白细胞介素 （IL）-23 是一种对诱导促炎 Th17 细胞至关重要的细胞因子，降低了转录因子 T 细胞因子 1 （TCF1） 的表达。成熟 T 细胞中 TCF1 的条件缺失增加了 Th17 细胞的促炎潜力，即使在没有 IL-23 受体信号传导的情况下也是如此，并赋予稳态 Th17 细胞促炎潜力。相反，持续的 TCF1 表达降低了促炎性 Th17 的潜力。从机制上讲，TCF1 与 RORγt 结合，从而干扰其促炎功能，并编排了一个决定 Th17 细胞状态的调节网络。我们的研究结果确定 TCF1 是 Th17 细胞状态的主要决定因素，并为 Th17 驱动的炎症性疾病的治疗方法开发提供了重要的见解。