Helicase A determines the transcription program of Th17 lineage differentiation and Autoimmunity

Th17 lineage is governed by canonical transcriptional factors and plays a pivotal role in the pathogenesis of autoimmune diseases in both mice and humans. However, the precise orchestration of this transcriptional program remains poorly understood. Here we identified a positive correlation between the expression of Dhx9, a nuclear helicase, and Th17 lineage during the progression of autoimmune diseases. Conditional deletion of Dhx9 in T cells significantly reduced Th17 differentiation and ameliorated the symptoms in mouse models of experimental autoimmune encephalomyelitis (EAE) and rheumatoid arthritis (RA). Mechanistically, Dhx9 was essential for increasing chromatin accessibility at the Rorc and Il17 loci, thereby facilitating the binding of canonical factors SMAD2, SMAD3, STAT3 and IRF4 to drive the transcription of these two core Th17-specific genes. We additionally identified NONO as a novel regulator of Th17 differentiation that acts dependent on its interaction with DHX9. Meanwhile, IL-6/STAT3 signaling promotes Th17 cell differentiation by upregulating DHX9 expression. Importantly, we identified a small-molecule inhibitor of Dhx9, punicalagin, which effectively suppressed Th17 differentiation and EAE progression. These findings uncover a novel mechanism orchestrating the transcriptional program of Th17 lineage commitment and highlight its therapeutic potential for autoimmune disease intervention.

Th17细胞谱系（Th17 lineage）受经典转录因子调控，并在小鼠与人类自身免疫疾病的发病过程中发挥关键作用。然而，该转录程序的精确调控机制仍未被充分阐明。本研究发现，在自身免疫疾病进程中，核解旋酶Dhx9的表达与Th17细胞谱系呈正相关。在T细胞中条件性敲除Dhx9，可显著抑制Th17细胞分化，并改善实验性自身免疫性脑脊髓炎（EAE）与类风湿关节炎（RA）小鼠模型的症状。从机制上看，Dhx9对增强Rorc与Il17基因座的染色质开放性至关重要，从而促进经典转录因子SMAD2、SMAD3、STAT3及IRF4的结合，以驱动这两个Th17细胞核心特异性基因的转录。本研究还发现，NONO是一种新的Th17细胞分化调控因子，其功能依赖于与DHX9的相互作用。与此同时，IL-6/STAT3信号通路可通过上调DHX9的表达，促进Th17细胞分化。值得注意的是，本研究发现了一种Dhx9的小分子抑制剂鞣云实素（punicalagin），其可有效抑制Th17细胞分化与EAE病情进展。本研究揭示了调控Th17细胞谱系定型转录程序的全新机制，并凸显了其在自身免疫疾病干预中的治疗潜力。