Retinoic acid promotes IgA antibody responses by boosting B cell TGF-β-induced germline Iα-Cα transcription, the expression of Smad3, Runx2, Tgfbr1 and Blimp-1-mediated plasma cell differentiation

Retinoic acid (RA), a dynamic derivative of vitamin A, has been recognized to exert a protective role against viral and bacterial infections, mainly by enabling IgA responses, thus critically contributing to gut and systemic immune homeostasis. We found that RA enhances T-dependent and T-independent IgA antibody responses.  In in vitro experiments, we showed that RA directly impacts B cells to increase CSR to IgA and IgA plasma cell differentiation.  RA boosts B cell Smad3 and Runx2 expression, which are recruited to Igα locus Iα promoter, thereby activating germline Iα-Cα transcription and increasing TGF-β-mediated CSR to IgA. RA also promotes Tgfbr1 (TGFBR1), a novel IgA response-associated gene, and Prdm1 expression, thereby further increasing B cell response to TGF-β as well as differentiation to IgA plasma cell, as confirmed by next-generation sequencing analysis of upregulated differentially expressed genes (DEGs).  Additional cell and biochemical experiments showed that RA activates gene expression by interacting with nuclear RA receptor (RAR)α which binds to DNA RA response elements (RAREs) in promoter of Iα as well as promoter and enhancer regions of Smad3, Runx2, Tgfbr1 and Prdm1 loci. Indeed, RARa knockdown in activated B cells impaired CSR to IgA and IgA plasma cell differentiation. Thus, by promoting activation of CSR to IgA and IgA plasma cell differentiation genes, RA plays a central role in IgA responses and provides an important therapeutic mediator.