title: Interleukin-23-Induced Transcription Factor Blimp-1 Promotes Pathogenicity of T Helper 17 Cells.
abstract: Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome-wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORγt, STAT-3, and p300 at the Il23r, Il17a/f, and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORγt to activate the Th17 inflammatory program.
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Renu
authors.initials: R
authors.lastname: Jain
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, & Musculoskeletal and Skin Diseases, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kanno
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Joyce-Shaikh
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, & Musculoskeletal and Skin Diseases, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: Golnaz
authors.initials: G
authors.lastname: Vahedi
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, & Musculoskeletal and Skin Diseases, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hirahara
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Blumenschein
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Sukumar
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Haines
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Sadekova
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Terrill K
authors.initials: TK
authors.lastname: McClanahan
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Mandy J
authors.initials: MJ
authors.lastname: McGeachy
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, & Musculoskeletal and Skin Diseases, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA. Electronic address: daniel.cua@merck.com.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cua
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D060888:Real-Time Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: D053759:Interleukin-23; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1