Tissue and age-related factors shape the antiviral T cell response in humans. Homo sapiens

Human immune responses to viruses are heterogeneous, and can vary over age, sex, and for different infection types. Here, we elucidate how human antiviral T cell immunity is maintained and functions over age and diversity by a comprehensive profiling of virus-specific T cells across blood, multiple lymphoid organs, and mucosal tissues of organ donors. We used flow cytometry, T cell receptor clonal analysis, single-cell transcriptomic, and functional analysis to characterize virus-specific CD8+ T cells recognizing ubiquitous viruses-influenza and cytomegalovirus. Our results reveal that virus-specific T cell immunity is controlled on multiple levels-the virus itself determines tissue distribution, differentiation, and clonal repertoire. Age and sex influence T cell differentiation and dissemination in tissues, including bone marrow, spleen, lung, and lung-associated lymph node, but not in blood. Transcriptional and cytokine profiling reveal that T cell functionality is highly correlated with the tissue site. Together, our results demonstrate that virus, tissue, age, and sex direct specific and measurable influences on antiviral immune responses that together influence functionality and protective efficacy.