title: STAT6-dependent regulation of Th9 development.
abstract: Th cell effector subsets develop in response to specific cytokine environments. The development of a particular cytokine-secreting pattern requires an integration of signals that may promote the development of opposing pathways. A recent example of this paradigm is the IL-9-secreting Th9 cell that develops in response to TGF-β and IL-4, cytokines that, in isolation, promote the development of inducible regulatory T cells and Th2 cells, respectively. To determine how the balance of these factors results in priming for IL-9 secretion, we examined the effects of each pathway on transcription factors that regulate Th cell differentiation. We demonstrated that TGF-β induces the PU.1-encoding Sfpi1 locus and that this is independent of IL-4-induced STAT6 activation. IL-4-activated STAT6 is required for repressing the expression of T-bet and Foxp3 in Th9 cells, transcription factors that inhibit IL-9 production, and STAT6 is required for the induction of IRF4, which promotes Th9 development. These data established a transcription factor network that regulates IL-9 and demonstrated how combinations of cytokine signals generate cytokine-secreting potential by altering the expression of a panel of transcription factors.
authors.affiliation: Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Ritobrata
authors.initials: R
authors.lastname: Goswami
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Jabeen
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yagi
authors.forename: Duy
authors.initials: D
authors.lastname: Pham
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhu
authors.forename: Shreevrat
authors.initials: S
authors.lastname: Goenka
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines; D053263:Gene Regulatory Networks; D050835:Interferon Regulatory Factors / Q000235:genetics; D015847:Interleukin-4 / Q000276:immunology; D016906:Interleukin-9 / Q000378:metabolism*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics; D015533:Transcriptional Activation; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4
chemical_list: D016207:Cytokines; D050835:Interferon Regulatory Factors; D015847:Interleukin-4; D016906:Interleukin-9; D011518:Proto-Oncogene Proteins; D050800:STAT6 Transcription Factor; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4; C494100:Stat6 protein, mouse