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

doi:10.1073/pnas.0705268104

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

*Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, 1-3, Yamada-oka, Suita, Osaka, 565-0871, Japan; and
^†Laboratory for Immune Signal, National Institute of Biomedical Innovation, 7-6-8, Saito Asagi, Ibaraki City, Osaka, 567-0085, Japan

Contributed by Tadamitsu Kishimoto, June 5, 2007 (received for review May 19, 2007)

Abstract

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.

Footnotes

^‡To whom correspondence should be addressed. E-mail: kishimot{at}imed3.med.osaka-u.ac.jp
Author contributions: T.N. and T.K. designed research; A.K. performed research; A.K., T.N., and T.K. analyzed data; and A.K., T.N., and T.K. wrote the paper.
The authors declare no conflict of interest.
Abbreviations:

DCCM,

conditioned medium from LPS-stimulated bone marrow-derived dendritic cells;

Foxp3,

forkhead box p3;

LPS,

lipopolysaccharides;

RORγt,

retinoid-related orphan receptor γt;

PMA,

phorbol 12-myristate 13-acetate;

Stat,

signal transducer and activator of transcription;

TGF-β,

transforming growth factor-β1;

Th17,

proinflammatory T helper cells producing IL-17.