TGF-β Signaling Initiated in Dendritic Cells Instructs Suppressive Effects on Th17 Differentiation at the Site of Neuroinflammation

While the role of Transforming Growth Factor β (TGF-β) as an intrinsic pathway has been well established in driving de novo differentiation of Th17 cells, no study has directly assessed the capacity of TGF-β signaling initiated within dendritic cells (DCs) to regulate Th17 differentiation. The central finding of this study is the demonstration that Th17 cell fate during autoimmune inflammation is shaped by TGF-β extrinsic pathway via DCs. First, we provide evidence that TGF-β limits at the site of inflammation the differentiation of highly mature DCs as a means of restricting Th17 cell differentiation and controlling autoimmunity. Second, we demonstrate that TGF-β controls DC differentiation in the inflammatory site but not in the priming site. Third, we show that TGF-β controls DC numbers at a precursor level but not at a mature stage. While it is undisputable that TGF-β intrinsic pathway drives Th17 differentiation, our data provide the first evidence that TGF-β can restrict Th17 differentiation via DC suppression but such a control occurs in the site of inflammation, not at the site of priming. Such a demarcation of the role of TGF-β in DC lineage is unprecedented and holds serious implications vis-à-vis future DC-based therapeutic targets.

虽然转化生长因子β（Transforming Growth Factor β，TGF-β）作为内在通路驱动Th17细胞从头分化的作用已得到充分证实，但目前尚无研究直接评估树突状细胞（dendritic cells，DCs）内启动的TGF-β信号通路调控Th17分化的能力。本研究的核心发现是，自身炎症过程中Th17细胞的命运由TGF-β经由DCs介导的外在通路所塑造。第一，我们证实TGF-β可在炎症部位限制高度成熟DC的分化，以此抑制Th17细胞分化并控制自身免疫反应；第二，我们证明TGF-β仅在炎症部位调控DC的分化，而非在致敏部位；第三，我们发现TGF-β在前体阶段调控DC的数量，而非成熟阶段。尽管TGF-β的内在通路驱动Th17分化这一点毋庸置疑，但我们的数据首次证实，TGF-β可通过抑制DC来限制Th17分化，不过这种调控发生在炎症部位，而非致敏部位。这种对TGF-β在DC谱系中作用的明确划分前所未有，对于未来基于DC的治疗靶点具有重要意义。