title: STAT3 Impairs STAT5 Activation in the Development of IL-9-Secreting T Cells.
abstract: Th cell subsets develop in response to multiple activating signals, including the cytokine environment. IL-9-secreting T cells develop in response to the combination of IL-4 and TGF-β, although they clearly require other cytokine signals, leading to the activation of transcription factors including STAT5. In Th17 cells, there is a molecular antagonism of STAT5 with STAT3 signaling, although whether this paradigm exists in other Th subsets is not clear. In this paper, we demonstrate that STAT3 attenuates the ability of STAT5 to promote the development of IL-9-secreting T cells. We demonstrate that production of IL-9 is increased in the absence of STAT3 and cytokines that result in a sustained activation of STAT3, including IL-6, have the greatest potency in repressing IL-9 production in a STAT3-dependent manner. Increased IL-9 production in the absence of STAT3 correlates with increased endogenous IL-2 production and STAT5 activation, and blocking IL-2 responses eliminates the difference in IL-9 production between wild-type and STAT3-deficient T cells. Moreover, transduction of developing Th9 cells with a constitutively active STAT5 eliminates the ability of IL-6 to reduce IL-9 production. Thus, STAT3 functions as a negative regulator of IL-9 production through attenuation of STAT5 activation and function.
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202; mkaplan2@iupui.edu olsonmr@iupui.edu.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Olson
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Biochemistry and Immunology, University of Sao Paulo, Ribeirao Preto, 14049-900 São Paulo, Brazil; and.
authors.forename: Felipe Fortino
authors.initials: FF
authors.lastname: Verdan
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hufford
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Dent
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202 mkaplan2@iupui.edu olsonmr@iupui.edu.
authors.forename: Mark H
authors.identifier: http://orcid.org/0000-0002-2923-8245
authors.initials: MH
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D016906:Interleukin-9 / Q000096:biosynthesis / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: D007376:Interleukin-2; D015850:Interleukin-6; D016906:Interleukin-9; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D015847:Interleukin-4