title: Stat3 phosphorylation mediates resistance of primary human T cells to regulatory T cell suppression.
abstract: Human autoimmune diseases are characterized by systemic T cell dysfunction, resulting in chronically activated Th1 and Th17 cells that are inadequately suppressed by regulatory T cells (Tregs). IL-6, which is overexpressed in tissue and serum of patients with autoimmune diseases, inhibits human Treg function. We sought to determine the mechanism for the antitolerogenic properties of IL-6 by examining the signaling pathways downstream of IL-6R in primary human T cells. Inhibition of Stat3 signaling in MLCs containing IL-6 restores Treg-mediated suppression, demonstrating that IL-6-mediated loss of Treg suppression requires phosphorylation of Stat3. Cultures in which either effector T cells (Teffs) or Tregs were pretreated with Stat3 inhibitors indicate that phosphorylated (p)Stat3 is required in both T cell populations for IL-6-mediated reversal of Treg function. IL-21, which signals preferentially through pStat3, also reverses Treg suppression, in contrast to IL-27 and IFN-γ, which signal preferentially through Stat1 and do not inhibit Treg function. Interestingly, both Teffs and Tregs respond to IL-6 stimulation through strong Stat3 phosphorylation with minimal MAPK/Erk activation and moderate Stat1 phosphorylation. Finally, Teffs stimulated strongly through the TCR are also resistant to suppression by Tregs and show concurrent Stat3 phosphorylation. In these cultures, inhibition of pStat3 restores functional suppression by Tregs. Taken together, our findings suggest that an early dominance of Stat3 signaling, prior to subsequent T cell activation, is required for the loss of functional Treg suppression and that kinase-specific inhibitors may hold therapeutic promise in the treatment of autoimmune and chronic inflammatory diseases.
authors.affiliation: Department of Dermatology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH 44106, USA. wag@case.edu
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Goodman
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Young
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McCormick
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Cooper
authors.forename: Alan D
authors.initials: AD
authors.lastname: Levine
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D010766:Phosphorylation / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000378:metabolism / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution / Q000276:immunology
chemical_list: C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human