The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-γ-producing T helper 17 cells

Yan Wang; Jernej Godec; Khadija Ben-Aissa; Kairong Cui; Keji Zhao; Alexandra B Pucsek; Yun Kyung Lee; Casey T Weaver; Ryoji Yagi; Vanja Lazarevic

doi:10.1016/j.immuni.2014.01.002

The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-γ-producing T helper 17 cells

Immunity. 2014 Mar 20;40(3):355-66. doi: 10.1016/j.immuni.2014.01.002. Epub 2014 Feb 13.

Authors

Affiliations

¹ Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
² Department of Microbiology and Immunobiology, Harvard Medical School and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
³ Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
⁵ Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁶ Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
⁷ Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Core Binding Factor Alpha 2 Subunit / genetics
Core Binding Factor Alpha 2 Subunit / metabolism
Core Binding Factor Alpha 3 Subunit / genetics
Core Binding Factor Alpha 3 Subunit / metabolism
Core Binding Factor alpha Subunits / genetics
Core Binding Factor alpha Subunits / metabolism*
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / metabolism
Gene Expression
Genetic Loci
Interferon-gamma / biosynthesis*
Interferon-gamma / genetics
Mice
Mice, Knockout
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
Protein Binding
T-Box Domain Proteins / genetics
T-Box Domain Proteins / metabolism*
Th1 Cells / cytology
Th1 Cells / immunology
Th1 Cells / metabolism
Th17 Cells / cytology
Th17 Cells / immunology*
Th17 Cells / metabolism*

Substances

Core Binding Factor Alpha 2 Subunit
Core Binding Factor Alpha 3 Subunit
Core Binding Factor alpha Subunits
Nuclear Receptor Subfamily 1, Group F, Member 3
T-Box Domain Proteins
T-box transcription factor TBX21
Interferon-gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding