116 Strategies and mechanisms for vaccine induction of mucosal T cell immunity

Abstract

Most HIV transmission is through mucosal surfaces. We previously found in mice that CD8 T cells must be in the local mucosa to prevent mucosal viral transmission. Intrarectal delivery was most effective, but not so practical. We devised a strategy to mimic intrarectal delivery through the oral route by encapsulating antigens in nanoparticles enclosed in microparticles that protected against stomach acid and enzymes and released the nanoparticles in the large intestine for update by dendritic cells. Different formulations resulted in selective release in the small or large intestine and T cell immunity in those sites, revealing a heretofore unknown subcompartmentalization between the small and large intestinal mucosal immune system. Delivery to the colon mimicked intrarectal delivery for protection of mice against intrarectal vaccinia virus challenge. We translated this to macaques, showing similar selective delivery and some preliminary evidence of efficacy in a SHIV intrarectal challenge model. The subcompartmentalization also implies that the homing receptors for T cells to traffic to the small and large intestine must differ. We found that indeed, small intestinal DCs induce T cells to home to the small intestine, whereas colonic DCs induce homing to the colon. This difference appears to correlate with different levels of retinoic acid production and differential induction of homing integrins and chemokine receptors. Besides the ability to mimic the benchmark intrarectal immunization by a more acceptable route, such subcompartmentalization may be useful for selective immunization, and understanding the mechanisms involved in homing may allow selective targeting of T cells to the right compartment.