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

• DOI: 10.1073/pnas.0705268104
• Publication Date: 2007-07-11T02:18:23Z
• Authors: Akihiro Kimura; Tetsuji Naka; Tadamitsu Kishimoto
• Keywords: STAT3 Transcription Factor; Receptors, Thyroid Hormone; Interleukin-6; Receptors, Retinoic Acid; Interleukin-17; Interleukin-1beta; Cell Differentiation; Dendritic Cells; T-Lymphocytes, Helper-Inducer; Nuclear Receptor Subfamily 1, Group F, Member 3; Mice, Inbred C57BL; Interferon-gamma; Mice; 03 medical and health sciences; STAT1 Transcription Factor; 0302 clinical medicine; Gene Expression Regulation; Animals; Humans; Cell Lineage; Female; RNA, Messenger

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-α or IL-1β, can, in combination with TGF-β, induce Th17 cell generation from naïve T cells and inhibit TGF-β-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-β could maintain activation of signal transducer and activator of transcription (Stat)3, but not of Stat1. IL-27 or IFN-γ suppressed the induction of Th17 cells by TGF-β 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.