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

Abstract

Abstract Lung tissue resident memory CD8 T cells (TRM) are critical for protection against heterologous influenza virus challenge by promoting rapid viral clearance. Unlike other mucosal tissues, we have found that local environmental signals are insufficient for the establishment of lung TRM, and that pulmonary antigen encounter is necessary for TRM to differentiate in the lung. Therefore, we investigated the role of lung antigen presenting cell (APC) subsets in the establishment of lung CD8 TRM following influenza infection. The initial appearance of flu-specific CD8 T cells in the lung with a TRM phenotype begins around day 10 post-infection, which coincides with viral clearance. Correspondingly, while most lung APC subsets contain influenza antigens over the course of infection, monocytes are the most numerous lung APC subset containing influenza antigens at the time of TRM appearance. Furthermore, imaging shows direct interaction between monocytes and T cells in the lung, supporting the idea that monocytes can act as drivers of lung TRM differentiation. In a murine influenza model, CCR2−/− mice, which have a defect in monocyte recruitment to the lung, had significantly fewer 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, indicating this effect is specific for tissue-resident memory cells. In addition, this phenotype is not driven by a lack of CCR2 on T cells, as adoptive transfer of wild-type OT-I T cells into CCR2−/− mice yields the same deficiency of lung TRM. Thus, these data show that antigen presentation by lung CCR2+ monocytes has an important role in the establishment of lung CD8 TRM.