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

• Published in: Immunity (Cambridge, Mass.) Vol. 50; no. 1; pp. 106 - 120.e10
• Main Authors: Schwartz, Daniella M., Farley, Taylor K., Richoz, Nathan, Yao, Chen, Shih, Han-Yu, Petermann, Franziska, Zhang, Yuan, Sun, Hong-Wei, Hayes, Erika, Mikami, Yohei, Jiang, Kan, Davis, Fred P., Kanno, Yuka, Milner, Joshua D., Siegel, Richard, Laurence, Arian, Meylan, Françoise, O’Shea, John J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.01.2019; Elsevier Limited
• Subjects: Acids; Animals; Asthma; ATAC-seq; CD4 antigen; ChIP-seq; Cytokines; Differentiation; Enhancers; Epigenetic Repression; Gene expression; Gene silencing; Genomes; HEK293 Cells; Helper cells; Humans; Hypersensitivity; Hypersensitivity - genetics; Hypersensitivity - immunology; Immune response; Immune system; Immunity; Inflammation; Interleukin 9; Interleukin-9 - metabolism; Interleukins; Lung - pathology; Lung - physiology; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumonia - genetics; Pneumonia - immunology; Retinoic acid; Retinoic Acid Receptor alpha - genetics; Retinoic Acid Receptor alpha - metabolism; RNA sequencing; Signal Transduction; Software; T helper cells; T-Lymphocytes, Helper-Inducer - physiology; Th9 cells; Transcription factors; Transcription, Genetic; Tretinoin - metabolism; Tumor necrosis factor-TNF; Vitamin A; RNA sequencing; Enhancers; vitamin A; Interleukins; ChIP-seq; T helper cells; Th9 cells; Retinoic acid; ATAC-seq; Interleukin 9
• ISSN: 1074-7613; 1097-4180; 1097-4180
• 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. [Display omitted] •Global effects of retinoic acid (RA) were evaluated by RNA sequencing in major Th subsets•RA impacts the transcriptome of Th9 cells more so than that of other effector subsets•RA-RARα represses the Il9 locus and Th9 program independently of Foxp3•RA-RARα activity controls pathology in Th9-associated allergic lung disease Schwartz et al. examine the impact of retinoic acid (RA) on the genome-wide transcriptional response during differentiation of CD4+ T cells to different Th subsets, revealing a role for RA in repressing the Th9 differentiation program. Their findings argue for the importance of this dietary metabolite in immune homeostasis and in Th9-associated inflammatory disease.