CD38 regulates age-dependent protective and pathological functions of CD8+ TRM cells 4567

Description Aging increases susceptibility to persistent pathology and sustained inflammation following respiratory viral infections. Our previous work demonstrated that this pathology is associated with excessive CD8+ tissue-resident memory T cell (TRM) responses. However, the mechanisms driving abnormal TRM accumulation and pathological activity remain unclear. In this study, we found that CD8+ TRM cells from influenza-infected young and aged mice express elevated CD38 levels, with aging further enhancing this expression. We also observed an increased frequency of CD38+ CD8+ TRMs in the BAL of elderly human patients following SARS-CoV-2 infection, where this increase inversely correlated with lung function. Furthermore, anti-CD38 treatment in influenza-infected aged mice reduced lung pathology, improved lung function, and decreased CD8+ TRM numbers, suggesting CD38 expression on CD8+ TRM drives pathology during aging. Experiments with influenza virus-infected young CD38KO mice, mixed bone marrow chimeras (WT x CD38KO), and CD38fl/flCD8cre mice revealed that CD38 intrinsically defines CD8+ TRM maintenance and responses after viral clearance. Additionally, CD38KO mice rechallenged with X31 influenza were more susceptible to infection than WT mice, suggesting reduced TRM numbers impair protective immunity in young mice. These findings reveal that CD38 expression on CD8+ TRM has age-related protective or pathological impacts on lung responses during influenza infection.