Repeated Antigen Exposure Extends the Durability of Influenza-Specific Lung-Resident Memory CD8+ T Cells and Heterosubtypic Immunity

Lung-resident primary memory CD8+ T cell populations (Trm) induced by a single influenza infection decline within months, rendering the host susceptible to new heterosubtypic influenza infections. Here, we demonstrate that, relative to single virus exposure, repeated antigen exposure dramatically alters the dynamics of influenza-specific lung Trm populations. Lung Trm derived from repeatedly stimulated circulating memory CD8+ T cells exhibit extended durability and protective heterosubtypic immunity relative to primary lung Trm. Parabiosis studies reveal that the enhanced durability of lung Trm after multiple antigen encounters resulted from the generation of long-lasting circulating effector memory (Tem) populations, which maintained the ability to be recruited to the lung parenchyma and converted to Trm, in combination with enhanced survival of these cells in the lung. Thus, generating a long-lasting Trm precursor pool through repeated intranasal immunizations might be a promising strategy to establish long-lasting lung Trm-mediated heterosubtypic immunity against influenza. [Display omitted] •Influenza-specific quaternary (4°M) lung Trm persist longer than 1°M Trm•Circulating 4°M CD8+ T cells have prolonged Tem phenotype compared to 1°M CD8+ T cells•Circulating 4°M Tem exhibit sustained migration to the lung and conversion to Trm•Prolonged lung 4°M Trm maintenance extends heterosubtypic immunity to influenza Van Braeckel-Budimir et al. find that repeated antigen exposure by influenza virus infection in the lung enhances the durability of lung CD8+ T resident memory populations and extends the duration of heterosubtypic immunity against influenza virus.