International Immunology Advance Access originally published online on May 9, 2007
International Immunology 2007 19(6):695-702; doi:10.1093/intimm/dxm045
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IL-6–gp130–STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state
1 Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan
2 Santen Pharmaceutical Co., Osaka, Japan
3 Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
4 Preclinical Research and Development, Merck KGaA, 64293 Darmstadt, Germany
5 Laboratory of Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan
Correspondence to: T. Hirano; E-mail: hirano{at}molonc.med.osaka-u.ac.jp
IL-17-producing Th (Th17) comprise a distinct lineage of pro-inflammatory Th that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor ß (TGFß) induces naive CD4+ T cells to generate Th17, which also requires expression of the IL-6/TGFß target ROR
t. We reported that IL-6 transduces two signaling pathways via tyrosine redidues of the signal transducer gp130: one depends on signal transducers and activators of transcription (STAT)-3 activation and the other on Src homology region 2 domain-containing phosphatase 2 (SHP2)/Grb2 associated binder (Gab)/mitogen-activated protein kinase (MAPK) activation. Here, we showed that CD4+ T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into Th17, while CD4+ T cells whose mutant gp130 transduces the STAT3 signal only generated Th17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of Th17. Moreover, we found that gp130–STAT3 pathway is essential for Th17 development and for the expression of RORt by using T cells specifically lacking gp130 and STAT3. Noteworthy is that the regulatory T cell (Treg) percentages and numbers were comparable between all mutant mice we tested in vivo, although we showed that IL-6–gp130–STAT3 pathway suppressed Treg development in vitro. Thus, we conclude that IL-6 acts directly to promote the development of Th17 by activating the T cell gp130–STAT3 pathway but has a minimum effect on Treg development at least in the steady state in vivo. Therefore, blockade of IL-6–gp130–STAT3 pathway in CD4+ T cells could be a good target for controlling unwanted Th17-mediated immune responses including autoimmune diseases.
Keywords: IL-6, gp130, STAT3, Th17, Treg
* These authors contributed equally to this study.
Received 7 March 2007, accepted 22 March 2007.
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