Heterogeneity of Human Anti-Viral Immunity Shaped by Virus, Tissue, Age, and Sex

The persistence of anti-viral immunity throughout the human body is essential for protection, and exhibits profound heterogeneity across individuals. Here, we elucidate the factors that shape the maintenance and function of anti-viral T cell immunity by comprehensive profiling of virus-specific T cells across blood, lymphoid organs, and mucosal tissues of organ donors. We used flow cytometry, T cell receptor analysis, single-cell transcriptomics, and cytokine analysis to profile virus-specific CD8+ T cells recognizing ubiquitous pathogens influenza and cytomegalovirus. Our results reveal that virus specificity determines the overall magnitude, tissue distribution, differentiation, and clonal repertoire of virus-specific T cells. Age and sex influence T cell differentiation and dissemination in tissues, while T cell tissue residence and functionality is highly correlated with the site. Together, our results demonstrate how the covariates of virus, tissue, age, and sex impact the anti-viral immune response, important for targeting, monitoring, and predicting immune responses to existing and emerging viruses.