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

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

Author information

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: lazarevicv@mail.nih.gov.

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.

PMID:
24530058
PMCID:
PMC3965587
DOI:
10.1016/j.immuni.2014.01.002
[Indexed for MEDLINE]
Free PMC Article
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