title: Molecular antagonism and plasticity of regulatory and inflammatory T cell programs.
abstract: Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3(+) Treg cells was associated in immune responses. Although TGF-beta receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors RORgammat and ROR*. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3(+) Treg cells. STAT3 regulated Foxp3 downregulation, whereas STAT3, RORgamma, and ROR* were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs.
authors.affiliation: Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xuexian O
authors.initials: XO
authors.lastname: Yang
authors.forename: Roza
authors.initials: R
authors.lastname: Nurieva
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Martinez
authors.forename: Hong Soon
authors.initials: HS
authors.lastname: Kang
authors.forename: Yeonseok
authors.initials: Y
authors.lastname: Chung
authors.forename: Bhanu P
authors.initials: BP
authors.lastname: Pappu
authors.forename: Bhavin
authors.initials: B
authors.lastname: Shah
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Chang
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Schluns
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Watowich
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D014161:Transduction, Genetic; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D053773:Transforming Growth Factor beta1