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

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


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Epigenetic Repression
  • HEK293 Cells
  • Humans
  • Hypersensitivity / genetics
  • Hypersensitivity / immunology*
  • Interleukin-9 / metabolism
  • Lung / pathology
  • Lung / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pneumonia / genetics
  • Pneumonia / immunology*
  • Retinoic Acid Receptor alpha / genetics
  • Retinoic Acid Receptor alpha / metabolism*
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / physiology*
  • Transcription, Genetic
  • Tretinoin / metabolism


  • Interleukin-9
  • Retinoic Acid Receptor alpha
  • Tretinoin