TGF-β-Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

TGF-beta is required for both Foxp3(+) regulatory T cell (Treg) and Th17 commitment. Plasmacytoid DCs (pDC) have been shown to participate to both Treg and Th17 commitment as well. However, few studies have evaluated the direct effect of TGF-beta on pDC, and to our knowledge, no study has assessed the capacity of TGF-beta-exposed pDC to polarize naive CD4(+) T cells. In this paper, we show that TGF-beta-treated pDC favor Th17 but not Treg commitment. This process involves a TGF-beta/Smad signal, because TGF-beta treatment induced Smad2 phosphorylation in pDC and blockade of TGF-beta signaling with the SD208 TGF-beta RI kinase inhibitor abrogated Th17 commitment induced by TGF-beta b-treated pDC. Moreover, TGF-beta mRNA synthesis and active TGF-beta release were induced in TGF-beta-treated pDC and anti-TGF-beta Ab blocked Th17 commitment. Unexpectedly, TGF-beta treatment also induced increased IL-6 production by pDC, which serves as the other arm for Th17 commitment driven by TGF-beta-exposed pDC, because elimination of IL-6-mediated signal with either IL-6- or IL-6R alpha-specific Abs prevented Th17 commitment. The in vivo pathogenic role of TGF-beta-treated pDC was further confirmed in the Th17-dependent collagen-induced arthritis model in which TGF-beta-treated pDC injection significantly increased arthritis severity and pathogenic Th17 cell accumulation in the draining lymph nodes. Thus, our data reveal a previously unrecognized effect of TGF-beta-rich environment on pDC ability to trigger Th17 commitment. Such findings have implications in the pathogenesis of autoimmune diseases or immune responses against mucosal extracellular pathogens. The Journal of Immunology, 2011, 186: 6157-6164.