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 (T rm ) 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 T rm populations. Lung T rm derived from repeatedly stimulated circulating memory CD8 + T cells exhibit extended durability and protective heterosubtypic immunity relative to primary lung T rm . Parabiosis studies reveal that the enhanced durability of lung T rm after multiple antigen encounters resulted from the generation of long-lasting circulating effector memory (T em ) populations, which maintained the ability to be recruited to the lung parenchyma and converted to T rm , in combination with enhanced survival of these cells in the lung. Thus, generating a long-lasting T rm precursor pool through repeated intranasal immunizations might be a promising strategy to establish long-lasting lung T rm -mediated heterosubtypic immunity against influenza.