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Immunity. 2019 Jan 15;50(1):106-120.e10. doi: 10.1016/j.immuni.2018.12.014.

Retinoic Acid Receptor Alpha Represses a Th9 Transcriptional and Epigenomic Program to Reduce Allergic Pathology.

Author information

1
Molecular Immunology and Inflammation Branch, NIAMS, NIH, Rockville, MD 20892, USA; Genenetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, NIAID, NIH, Rockville, MD 20892, USA. Electronic address: daniella.schwartz@nih.gov.
2
Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Rockville, MD 20892, USA; Metaorganism Immunity Section, Laboratory of Immune System Biology, NIAID, NIH, Rockville, MD 20892, USA.
3
Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Rockville, MD 20892, USA.
4
Molecular Immunology and Inflammation Branch, NIAMS, NIH, Rockville, MD 20892, USA.
5
Genenetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, NIAID, NIH, Rockville, MD 20892, USA.
6
Office of Science and Technology, NIAMS, NIH, Rockville, MD 20892, USA.
7
Translational Gastroenterology Unit, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, UK.

Abstract

CD4+ T helper (Th) differentiation is regulated by diverse inputs, including the vitamin A metabolite retinoic acid (RA). RA acts through its receptor RARα to repress transcription of inflammatory cytokines, but is also essential for Th-mediated immunity, indicating complex effects of RA on Th specification and the outcome of the immune response. We examined the impact of RA on the genome-wide transcriptional response during Th differentiation to multiple subsets. RA effects were subset-selective and were most significant in Th9 cells. RA globally antagonized Th9-promoting transcription factors and inhibited Th9 differentiation. RA directly targeted the extended Il9 locus and broadly modified the Th9 epigenome through RARα. RA-RARα activity limited murine Th9-associated pulmonary inflammation, and human allergic inflammation was associated with reduced expression of RA target genes. Thus, repression of the Th9 program is a major function of RA-RARα signaling in Th differentiation, arguing for a role for RA in interleukin 9 (IL-9) related diseases.

KEYWORDS:

ATAC-seq; ChIP-seq; Enhancers; Interleukin 9; Interleukins; RNA sequencing; Retinoic acid; T helper cells; Th9 cells; vitamin A

PMID:
30650370
PMCID:
PMC6338086
[Available on 2020-01-15]
DOI:
10.1016/j.immuni.2018.12.014

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