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

Int Immunol. 2007 Jun;19(6):695-702. doi: 10.1093/intimm/dxm045. Epub 2007 May 9.

Abstract

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 beta (TGFbeta) induces naive CD4+ T cells to generate Th17, which also requires expression of the IL-6/TGFbeta target RORgammat. 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 RORgammat 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / blood
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / pathology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Count
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Cytokine Receptor gp130 / genetics
  • Cytokine Receptor gp130 / physiology*
  • Flow Cytometry
  • Forkhead Transcription Factors / metabolism
  • Interleukin-17 / blood
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism*
  • Interleukin-6 / genetics
  • Interleukin-6 / pharmacology
  • Interleukin-6 / physiology*
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Mice, Transgenic
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Retinoic Acid / metabolism
  • Receptors, Thyroid Hormone / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-17
  • Interleukin-6
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • Rorc protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Cytokine Receptor gp130