Using Rexinoids to Program Effector T cells for Homing to Mucosal Sites of Virus Transmission

Abstract Vaccines are the most effective defense against infectious diseases. To be most successful, vaccines must target the induced immune response to chief sites of pathogen entry: epithelial and mucosal surfaces. We have previously shown that the biologically active form of Vitamin A, all-trans retinoic acid (ATRA), can directly modulate the expression of gut mucosal-homing receptors on T cells as binding of ATRA to the retinoic acid receptor (RAR), which partners with the retinoid X receptor (RXR), promotes transcription of specific genes. Rexinoids, synthetic ligands for the RXR, have potential to mimic or improve the immune effects of vitamin A by enhancing RAR-mediated transcription. Additionally, rexinoids have a greater potential for clinical use due to their improved solubility and stability, making them candidates to incorporate into vaccines. Here, we explored the possibility of different rexinoids to function as adjuvants during vaccination to program effector T cell expression of the gut-homing receptors CCR9, α4β7, and CD103. CD8 T cells obtained from transgenic mice were co-cultured with peptide and set concentration of each rexinoid, followed by flow cytometric analysis of receptor expression. We observed increased expression of gut-homing receptors during activation in the presence of certain rexinoids, indicating that they can mimic the effects of ATRA. Furthermore, we saw a cooperative relationship between other rexinoids and ATRA, as co-culturing with sub-optimal doses of each resulted in enhanced expression. Our findings lend support for the prospective use of these rexinoids as adjuvants during vaccination and in therapeutic approaches against diseases transmitted across mucosal surfaces.