Altered infant T cell differentiation in infection or vaccination reduces lung tissue-resident memory generation

Infants suffer disproportionately from respiratory infections and generate reduced vaccine responses compared to adults, although underlying mechanisms remain unclear. In adult mice, lung-localized, tissue-resident memory T cells (TRM) mediate optimal protection to respiratory pathogens. We hypothesized that reduced protection in infancy was due to impaired T effector localization and/or lung TRM establishment. Using an infant mouse model we demonstrate generation of lung-homing, virus-specific T effectors following influenza infection or live-attenuated vaccination, similar to adults. However, infection during infancy generated markedly fewer lung TRM and heterosubtypic protection was reduced compared to adults. Impaired TRM establishment was infant-T cell-intrinsic and infant effectors displayed distinct transcriptional profiles enriched for T-bet-regulated genes. Notably, mouse and human infant T cells exhibited increased T-bet expression following activation and reducing T-bet levels in infant mice enhanced lung TRM establishment. Our findings reveal that infant T cells are intrinsically programmed for short-term responses and targeting key regulators could promote long-term, tissue-targeted protection at this critical life stage. Transcriptional profiling by RNA-seq of infant and adult flu-specific mouse CD4 T cells. Project includes three biological replicates of both sample types.