IL-6-gp130-STAT3 in T cells directs the development of IL-17+ T sub(h) with a minimum effect on that of Treg in the steady state

IL-17-producing T sub(h) (T sub(h)17) comprise a distinct lineage of pro-inflammatory T sub(h) that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor {szligbeta} (TGF{szligbeta}) induces naive CD4 super(+) T cells to generate T sub(h)17, which also requires expression of the IL-6/TGF{szligbeta} target ROR gamma 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 super(+) T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into T sub(h)17, while CD4 super(+) T cells whose mutant gp130 transduces the STAT3 signal only generated T sub(h)17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of T sub(h)17. Moreover, we found that gp130-STAT3 pathway is essential for T sub(h)17 development and for the expression of ROR gamma t 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 T sub(h)17 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 super(+) T cells could be a good target for controlling unwanted T sub(h)17-mediated immune responses including autoimmune diseases.