Adjuvants orchestrate cross-organ induction of mucosal CD8+ T cell immune responses in respiratory tracts

Abstract Mucosal immunity is paramount for combating respiratory infections, but conventional vaccination methods, such as intramuscular injection, often struggle to induce it. Although direct mucosal vaccination is effective, it carries an increased risk of respiratory adverse effects, making it particularly challenging for individuals with chronic respiratory diseases. Consequently, developing a strategy to induce sufficient mucosal immune responses without modifying conventional vaccination methods would be highly desirable. The potential of vaccine adjuvants to facilitate such cross-organ induction of mucosal immunity, given their established role in enhancing and shaping immune responses, is currently not well understood. In this study, we investigated the effects of intramuscular vaccination using OVA or RBD-Fc formulated with four distinct adjuvants, aluminum hydroxide, squalene-based emulsion (AddaVax), STING agonist diamidobenzimidazole (diABZI), and immunostimulatory complexes (ISCOMs). All of these adjuvants increased serum antigen-specific IgG titers and correspondingly elevated IgG levels in bronchoalveolar lavage fluid (BALF), but their impact on mucosal IgA was limited. Interestingly, only ISCOMs significantly increased the proportion of pulmonary antigen-specific CD8+ T cells, a significant amount of which were in a tissue-resident memory phenotype. Subsequent mechanistic investigations showed that ISCOMs-activated dendritic cells promoted the expression of α4β1 integrin on CD8+ T cells, a key factor believed to mediate T cell residency in the lungs. Our findings indicate that judicious adjuvant selection can facilitate the induction of mucosal immune responses via intramuscular vaccination, a well-accepted and safer route.