Innate immune receptor engagement governs functional differentiation of effectors and persistence of tissue-resident memory T cells 4002

Abstract Description Inducing robust mucosal memory T cells in the lung is critical for developing vaccines against respiratory pathogens like Influenza A virus (IAV). Lung tissue-resident memory (TRM) cells serve as the first defense against IAV but undergo rapid attrition, challenging T cell-based mucosal vaccine strategies for durable immunity. This study examined the impact of combination adjuvants targeting distinct innate receptors on CD8 T cell differentiation and TRM persistence. Intranasal delivery of Adjuplex (ADJ) combined with either TLR4 agonist GLA or STING agonist CDN induced strong expansion of mucosally-imprinted CD8 T cells in lungs and airways. ADJ+GLA predominantly generated Type III T cells, while ADJ+CDN favored Type I T cells. ADJ+GLA vaccination led to the persistence of greater number of lung TRMs, correlated with sustained IL-7R expression and lower viral titers (180d p.v.). Also, ADJ+GLA but not IAV induced stem-like, functionally plastic Type III TRMs provided durable immunity to IAV. In Tbx21 conditional KO mice, ADJ+GLA increased IL-17A+, RORγt+, ICOS+, and CD127+ CD8 T cells, suggesting the roles of RORγT and T-bet in vaccine-induced TRM development. Ongoing studies aim to elucidate the precise role of T-bet and RORγT in durable TRM formation. In summary, innate receptor engagement shapes T cell differentiation and lung TRM durability. Our findings highlight Type III programming as a promising avenue for mucosal vaccine design against respiratory viral pathogens. Funding Sources This work was supported by Public Health Service Grants UO1AI12499 and R21AI173757 from the National Institutes of Health and the John E. Butler Professorship to MS. Topic Categories Vaccines and Immunotherapy (VAC)