title: Human CD39+TregCells Express Th17-Associated Surface Markers and Suppress IL-17 via a Stat3-Dependent Mechanism.
abstract: Human CD4+T regulatory cells (Tregs) are a population of phenotypically and functionally diverse cells that downregulate inflammatory and autoimmune responses. As Th17 cells play an important role in the pathogenesis of autoimmune diseases, it is critical to elucidate the mechanisms regulating these cells. In this study, we examined the molecular basis underlying the phenotypic and functional diversity of human Tregsexpressing the ectonucleotidase CD39. CD4+CD25hiCD39+Tregsinhibit the proliferative response and the secretion of IL-17 and IFN-γ of autologous CD4+T effector cells, while CD4+CD25hiCD39-Tregsonly suppress IFN-γ production. We demonstrate that activated human CD4+CD25hiCD39+Tregsexpress the Th17-associated surface markers CCR6 and IL-23R, and phosphorylate the transcription factor Stat3. Moreover, suppression of IL-17 by CD4+CD25hiCD39+Tregsoccurs via a Stat3-dependent mechanism as inhibition of Stat3 activation in the CD39+Tregsreverses their ability to suppress IL-17. CD4+CD25hiCD39-Tregsare not endowed with the ability to inhibit IL-17 as they do not upregulate CCR6 or the IL-23R, and furthermore, they secrete IL-17. Our findings provide the first evidence that human Tregfunctional diversity is matched to the type of immune response being regulated and reveal a new role for Stat3 in controlling Tregfunction.
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey-New Jersey Medical School , Newark, New Jersey.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Magid-Bernstein
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey-New Jersey Medical School , Newark, New Jersey.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Rohowsky-Kochan
mesh_terms: D000328:Adult; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000954:Antigens, Surface; D015415:Biomarkers; D016207:Cytokines; D020381:Interleukin-17; D050796:STAT3 Transcription Factor
keywords: CD39+ Treg cells; IL-17; Stat3