IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells

CD4(+) T cells producing IL-17 T helper (Th)17, as distinct from Th1 or Th2 cells, have recently been shown to be associated with autoimmunity, but it is not entirely clear how Th17 cells are generated from naïve T cells. We demonstrate here that IL-6, but not TNF-alpha or IL-1beta, can, in combination with TGF-beta, induce Th17 cell generation from naïve T cells and inhibit TGF-beta-induced Foxp3 expression. Moreover, conditioned medium from lipopolysaccharide-stimulated bone marrow-derived dendritic cells (DCCM) can induce IL-17 production in naïve T cells. Interestingly, IL-17 was produced by DCCM even with the addition of anti-gp130 antibody or DCCM from IL-6 KO mice. The combination of IL-6 and TGF-beta could maintain activation of signal transducer and activator of transcription (Stat)3, but not of Stat1. IL-27 or IFN-gamma suppressed the induction of Th17 cells by TGF-beta plus IL-6 and maintained Stat1 activation under these conditions. In contrast, both Stat1 and Stat3 remained to be activated in naïve T cells cultured with DCCM. These findings represent a different basis for Th17 differentiation from naïve T cells.