Decoding cellular networks governing respiratory mucosal IgA immunity

Abstract/summary The factors and mechanisms driving robust respiratory mucosal immunity, particularly respiratory IgA responses, post-infection or vaccination are largely unknown. This represents a significant gap in our understanding necessary for designing future vaccination strategies aimed at providing enhanced mucosal protection against respiratory viral infections including new SARS-CoV-2 variants. This RO1 grant proposal aims to address this critical knowledge gap. Our central hypothesis is that the generation of mucosal IgA and respiratory protective immunity is contingent upon the localized interactions among pulmonary macrophages, CD4 T cells, and B cells within the respiratory tract. Three specific aims (SA) are proposed. Aim 1: Identify the associated mechanisms by which respiratory CD4+ T cells promote IgA production in situ. Aim 2: Elucidate TGFβ-dependent macrophages and B cell interactions in mucosal IgA production. Aim 3: Define the molecular and functional signatures of mucosal cross-reactive IgA-producing B cells. We believe that the insights obtained will be crucial in developing next-generation mucosal vaccines designed to effectively counter SARS-CoV-2 variants and other respiratory pathogens, significantly enhancing public health prevention strategies against respiratory infections. .