Tissue-resident CD8+ T cells drive age-associated chronic lung sequelae after viral pneumonia.

Goplen, Nick P; Wu, Yue; Son, Young Min; Li, Chaofan; Wang, Zheng; Cheon, In Su; Jiang, Li; Zhu, Bibo; Ayasoufi, Katayoun; Chini, Eduardo N; Johnson, Aaron J; Vassallo, Robert; Limper, Andrew H; Zhang, Nu; Sun, Jie

Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-β present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia.