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MULTI-LEVEL REGULATION OF T HELPER CELLS BY RETINOIC ACID RECEPTOR ALPHA
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The active metabolite of vitamin A, retinoic acid, is a key mediator of balanced immune responses. The major nuclear receptor of retinoic acid, retinoic receptor alpha (RARα), functions as a transcriptional regulator, with both active and repressive effects on transcription depending on interactions with nuclear cofactors dictated by ligand-binding effects on protein confirmation. While significant advances have been made in understanding the combined effects of retinoic acid and RARα, the individual roles of each remain incompletely identified.
Epigenetic effects of all-trans retinoic acid (At-RA) and RARα on the transcriptome of T helper cells were assessed using a novel transgenic mouse strain designed to overexpress RARα in T cells and a conditional knock out strain in which RARα was specifically deleted from T cells. At-RA and RARα had divergent roles in promoting Th17 and Treg differentiation, with RARα expression favoring Th17 differentiation over Treg differentiation, and At-RA promoting Treg differentiation over Th17 differentiation. Transcriptome analysis identified groups of At-RA and RARα differentially regulated genes (DEGs). Comparison of these genes to the H3k27 acetylated and tri-methylated epigenetic modifications demonstrated that RARα expression increased the overall level of these epigenetic modifications in all DEG groups, with enhanced control of transcriptional regulation mediated by higher RARα expression. Additionally, expression of transcriptional repressors was strongly regulated by At-RA in a RARα-dependent manner and had repressive effects on the differentiation of T helper cells.
Immunometabolism was also enhanced by RARα expression, leading us to study potential non-genomic roles of RARα on signaling pathways. The major TCR signaling pathways were enhanced by RARα but suppressed by At-RA, suggesting a mechanism by which RARα regulates cellular metabolism upon T cell activation.
In summary, we identified distinct epigenetic and non-genomic effects of RARα as novel regulatory mechanisms by which vitamin A and retinoic acid influence immune responses. Further research into these findings, notably RARα involvement in signal transduction pathways of immune cells, will define how this research can be translated into clinically-relevant applications.