CD8+ T cell transcriptional reprogramming toward TCF7-low cytotoxicity drives immune aging in viral ARDS.

Viral acute respiratory distress syndrome (ARDS) exhibits distinct clinical outcomes across age groups, but the immune mechanisms underlying this disparity remain unclear. Here, we integrated single-cell transcriptomic profiling, T cell receptor repertoire analysis, serum proteomics, and functional validation to characterize age-dependent T cell remodeling in influenza-associated ARDS. Adult ARDS was characterized by reduced T cell receptor diversity, expansion of CD8+ effector memory T cells, and enhanced cytotoxic programs marked by increased granzyme B (GZMB) expression compared with pediatric ARDS. At the transcriptional level, adult CD8+ effector memory T cells displayed a TCF7-low state associated with activation of a TGFB1-related RUNX3/PRDM1 program. In vitro experiments further demonstrated that TGFB1 promoted cytotoxic programming in CD8+ effector memory T cells and increased epithelial injury in a co-culture model. These findings identify age-associated CD8+ T cell remodeling as a potential mechanism contributing to immune dysregulation in viral ARDS.