Tissue-resident monocytes promote the establishment of lung-resident CD8 T cell memory following influenza infection

Abstract

Abstract Lung tissue resident memory CD8 T cells (TRM) have been shown to be critical in protecting against heterologous influenza virus challenge by limiting early viral replication and promoting more rapid viral clearance. Unlike other mucosal tissues, we have found that environmental signals are insufficient for the establishment of lung TRM, and that pulmonary antigen encounter is necessary for TRM to differentiate in the lung. This indicates a likely role for pulmonary antigen presenting cells (APC’s) in the process of lung TRM development, and thus we investigated the role of lung APC subsets on the establishment of lung CD8 TRM following influenza infection. Although many lung APC subsets contain flu nucleoprotein (FluNP) over the course of infection, most lung APC’s do not contain FluNP once virus has been cleared by day 10 post-infection. In contrast, lung monocytes continue to have high numbers of FluNP-bearing cells through day 15 post infection, the same time we observe the appearance of flu-specific CD8 T cells with a TRM phenotype. As these data suggest a potential role for monocytes as drivers of TRM differentiation, we tested mice deficient for the chemokine receptor CCR2 (CCR2−/−), which have a significant defect in the recruitment of monocytes to the lung. In our murine influenza model these CCR2−/− mice had significantly less flu-specific lung CD8 TRM than WT controls. Notably, this defect was not observed in the flu-specific CD8 memory T cells in the lung vasculature or mediastinal lymph node (MedLN), indicating this effect is specific for tissue-resident memory cells. Thus, these data show that antigen presentation by CCR2+ monocytes have a likely role in the lung in the establishment of lung CD8 TRM.