Novel Vaccine Adjuvants: Exploring the Potential of Rexinoids to Influence Effector T Cell Homing to Mucosal Sites

Abstract Vaccines are the most successful defense against infectious diseases. Effective vaccines must target induced immune responses to areas of pathogen entry, a primary site being mucosal surfaces. Certain vitamins can directly impact immune cell migration, indicating potential to function as an adjuvant. We previously showed that all-trans retinoic acid (ATRA), the biologically active form of vitamin A, modifies gut-homing receptor expression on effector T cells upon binding to the retinoic acid receptor (RAR), which joins with the retinoid X receptor (RXR) to function. Giving ATRA during vaccination also resulted in enhanced mucosal protection following viral challenge in murine models. While promising, certain factors limit adding ATRA to a vaccine, including its instability and poor solubility. Rexinoids, synthetic ligands for the RXR, could mimic or better ATRA immune effects by enhancing RAR-mediated transcription. Their improved stability and solubility also allows a greater potential for clinical use. Here we explored the ability of different rexinoids to program effector T cell expression of gut-homing receptors CCR9, α4β7, and CD103. Naïve T cells from transgenic mice were activated with peptide and set concentration of each rexinoid. Flow cytometry showed increased expression of gut-homing receptors in the presence of select rexinoids, indicating their ability to act as an ATRA mimic. A cooperative relationship was also seen between other rexinoids and ATRA as co-culturing with suboptimal doses of each showed enhanced receptor expression, suggesting these rexinoids could potentially act with ATRA normally found in serum. Overall, our findings support the prospective use of rexinoids as adjuvants during vaccination.