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

Respiratory viral infections establish tissue-resident memory T cells (T_RM) in the lung, which provide optimal protection against subsequent infections, though the underlying mechanisms are incompletely understood. Here, we demonstrate in a mouse model of heterosubtypic influenza infection that lung T_RM attenuate inflammation by macrophages during secondary versus primary responses, in part, through production of the immunoregulatory cytokine IL-10. During secondary infections, lung T_RM were the predominant producers of early IL-10; inhibiting early IL-10 signaling resulted in increased macrophage-mediated inflammation, morbidity, and lung pathology. Moreover, lung T_RM were shown to directly modulate lung macrophage responses and polarization in depletion experiments. Finally, IL-10 enhanced IFN-γ production by lung memory CD8⁺ T cells. Human influenza-specific T_RM isolated from lungs recapitulated robust IL-10 expression associated with augmented effector responses of murine T_RM. These data support a dual role of T_RM in coordinating in situ secondary responses—augmenting effector responses for robust viral clearance while dampening inflammation to limit tissue damage.