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TGF- signaling initiated in dendritic cells instructs suppressive effects on Th17 differentiation at the site of neuroinflammation

Speck, S;Lim, J;Shelake, S;Matka, M;Stoddard, J;Farr, A;Kuchroo, V;Laouar, Y;

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