Local immune networks promote respiratory IgA responses after mucosal vaccination 2260370

Abstract Introduction Mucosal immunization and respiratory IgA offer significant promise in protecting against airborne pathogens, including SARS-CoV-2. However, the conditions and mechanisms that lead to the robust induction of respiratory IgA responses following mucosal vaccination remain poorly understood. Methods In this project, we established SARS-CoV-2 breakthrough infection and mucosal adenovirus-based booster vaccination models. Using genetic mouse models and various in vivo and in vitro blockade or depletion approaches, we further investigated the mechanisms regulating respiratory IgA responses. Results Here we found that a mucosal adenovirus-based booster vaccination in mouse models revealed that respiratory booster immunization elicited markedly stronger and more durable respiratory IgA, T cell response, and protective immunity against SARS-CoV-2, supporting the promise of respiratory mucosal vaccination. Mechanistically, we identified that local CD4+ T cells support respiratory IgA production by promoting IgA+ B cell class switching, proliferation, and survival in situ. This T cell help depended on interactions between local Blimp-1+ T-bet+ Th1 cells and B cells, mediated through ICOS/CD40L/MHC-II engagement and IL-21 signaling. Furthermore, lung macrophages contributed to the mucosal IgA response via TGF-β production. Consequently, mucosal administration of SARS-CoV-2 Spike-encoding mRNA encapsulated in pulmonary surfactant (PS)- incorporated lipid nanoparticles designed to target lung macrophages elicited a stronger mucosal IgA response. Conclusion Our results uncover a local cellular network supporting enhanced mucosal IgA responses, with implications for the development of optimal mucosal immunization strategies against SARS-CoV-2 and other respiratory pathogens such as H5N1 influenza. Funding Source AI147394, AG069264, AI112844, HL170961, AI154598, AI176171 to J.S., AI67986, AI177467 to Hui.H; U54CA260582 to S.L.L; R01AI168684 to G. Z.; S.L.L was also supported by a fund provided by an anonymous private donor to The Ohio State University. Topic Categories Mucosal and Regional Immunology (MUC)