Lung tissue-resident memory T cells optimize protection by IL-10 regulation of innate immunity

Respiratory viral infections establish tissue resident memory T (TRM) cells in the lung, which provide optimal protection against infectious challenge, though the underlying mechanisms remain incompletely understood. Here, using a mouse model of heterosubtypic influenza infection, we demonstrate that the lung-localized secondary immune response exhibits an attenuated innate immune response compared to the primary response due to TRM-mediated production of the immunoregulatory cytokine IL-10. Using reporter mice, we identify that lung TRM are the predominant producers of early IL-10 in response to viral challenge. Inhibition of early IL-10 signaling in secondary infections results in increased morbidity and lung pathology, and reveals pleiotropic effects of IL-10 in regulating macrophage inflammation and enhancing IFN-g production by memory CD8+T cells. Human influenza-specific TRM isolated from lungs recapitulate robust IL-10 expression associated with augmented effector responses of murine TRM. These data support a dual role for TRM in coordinating in situ secondary responses - augmenting effector responses for robust viral clearance while dampening inflammation to limit tissue damage.