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

Abstract

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.

Neural precursor cell–secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity

“…TGF-β signaling is necessary to prevent autoimmunity (81), and the signaling through the TGFBRs in DCs is a prerequisite to control EAE autoimmune response (82). Moreover, 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 (83).…”

TGFβ regulates persistent neuroinflammation by controlling Th1 polarization and ROS production via monocyte‐derived dendritic cells

“…This T cell subset was critical in disease initiation, whereas NK cells and microglia played no role in that model. Furthermore, TGFβ was demonstrated to be a potent suppressor of DC derivation by GM‐CSF, but not of DC activation by LPS (Speck et al, ).…”

“…TGFb is a pleiotropic cytokine with important functions during embryogenesis, patterning, development, homeostasis, and repair. TGFb activity increases dramatically in the CNS during EAE, as elegantly demonstrated by in vivo bioluminescence studies (Luo et al, 2007;Lanz et al, 2010;Speck et al, 2014). Attempts to define the role of TGFb during EAE have yielded conflicting results.…”

Treg Heterogeneity, Function, and Homeostasis

“…They can suppress the activation and proliferation of effector T and B lymphocytes; they can also directly induce pTregs and Bregs (75)(76)(77)(78). In addition, TGF-β and IL-10 inhibit antigenic presentation to stimulate the generation of tolerogenic dendritic cells, which in their turn enable pTreg induction (79)(80)(81)(82)(83). Note that two pTreg populations have been well-described: Th3 and Tr1, featuring high TGF-β, and IL-10 secretion, respectively.…”