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

While the role of Transforming Growth Factor b (TGF-b) 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-b 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-b extrinsic pathway via DCs. First, we provide evidence that TGF-b 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-b controls DC differentiation in the inflammatory site but not in the priming site. Third, we show that TGF-b controls DC numbers at a precursor level but not at a mature stage. While it is undisputable that TGF-b intrinsic pathway drives Th17 differentiation, our data provide the first evidence that TGF-b 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-b in DC lineage is unprecedented and holds serious implications vis-à-vis future DC-based therapeutic targets