RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells whose upregulation in developing Th17 cells is critically regulated by interleukin-6 (IL-6) and TGF-β, the molecular mechanisms of which remain largely unknown. Here we identified conserved non-coding sequences (CNSs) 6 and 9 at the Rorc gene, essential for its expression during Th17 cell differentiation but not required for RORγt expression in innate lymphocytes and γδ T cells. Mechanistically, the IL-6-signal transducer and activator of transcription 3 (STAT3) axis appeared to be largely dependent on CNS9 and only partially on CNS6 in controlling RORγt expression and epigenetic activation of the Rorc locus. TGF-β alone was sufficient to induce RORγt expression in a CNS6- but not CNS9-dependent manner through CNS6 binding by SMAD proteins. Our study reveals an important synergistic mechanism downstream of IL-6 and TGF-β in regulation of RORγt expression and Th17 cell commitment via distinct cis-regulatory elements.

RORγt是T辅助细胞17（Th17）细胞的谱系特异性转录因子，其在发育中的Th17细胞中的上调受到白介素6（IL-6）和TGF-β的严格调节，其分子机理尚不清楚。在这里，我们在Rorc基因上鉴定了保守的非编码序列（CNSs）6和9 ，这对于在Th17细胞分化过程中表达至关重要，但对于先天淋巴细胞和γδT细胞中RORγt表达而言则不是必需的。从机制上讲，IL-6信号转导子和转录激活子3（STAT3）轴似乎在控制RORγt表达和Rorc的表观遗传激活方面很大程度上依赖于CNS9，而仅部分依赖于CNS6。轨迹。单独的TGF-β足以通过SMAD蛋白与CNS6结合，以CNS6-依赖性方式诱导RORγt表达，但不足以诱导CNS9依赖性方式。我们的研究揭示了IL-6和TGF-β下游通过不同的顺式调控元件调控RORγt表达和Th17细胞表达的重要协同机制。