title: The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-γ-producing T helper 17 cells.
abstract: T helper 17 (Th17) cells can give rise to interleukin-17A (IL-17A)- and interferon (IFN)-γ-double-producing cells that are implicated in development of autoimmune diseases. However, the molecular mechanisms that govern generation of IFN-γ-producing Th17 cells are unclear. We found that coexpression of the Th1 and Th17 cell master transcription factors, T-bet and retinoid-related orphan receptor gamma-t (RORγt), respectively, did not generate Th cells with robust IL-17 and IFN-γ expression. Instead, development of IFN-γ-producing Th17 cells required T-bet and Runx1 or Runx3. IL-12-stimulated Th17 cells upregulated Runx1, which bound to the Ifng locus in a T-bet-dependent manner. Reciprocally, T-bet or Runx1 deficiency or inhibition of Runx transcriptional activity impaired the development of IFN-γ-producing Th17 cells during experimental autoimmune encephalomyelitis, which correlated with substantially ameliorated disease course. Thus, our studies identify a critical role for T-bet and Runx transcription factors in the generation of pathogenic IFN-γ-producing Th17 cells.
authors: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Yan
authors: Y
authors: Wang
authors: Department of Microbiology and Immunobiology, Harvard Medical School and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Jernej
authors: J
authors: Godec
authors: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Khadija
authors: K
authors: Ben-Aissa
authors: Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Kairong
authors: K
authors: Cui
authors: Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Keji
authors: K
authors: Zhao
authors: Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors: Alexandra B
authors: AB
authors: Pucsek
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Yun Kyung
authors: YK
authors: Lee
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Casey T
authors: CT
authors: Weaver
authors: Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors: Ryoji
authors: R
authors: Yagi
authors: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: lazarevicv@mail.nih.gov.
authors: Vanja
authors: V
authors: Lazarevic
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism; D050657:Core Binding Factor alpha Subunits / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D056426:Genetic Loci; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; D050657:Core Binding Factor alpha Subunits; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma