Grenfell, Bryan T.Lin, Johnson2025-08-042025-08-042025-04-28https://theses-dissertations.princeton.edu/handle/88435/dsp01cn69m757pImmunosenescence, or immune system aging, has profound implications on infection susceptibility, vaccine efficacy, and immune resilience across the human lifespan. Despite extensive cross-sectional studies, little is known about how aging shapes CD8+ T cell subsets and their antigen-specific functionality in a longitudinal context. In this study, we employed a multi-omics approach integrating gene expression, surface proteomics, and TCR sequencing to characterize immunosenescence. CD8+ T cells were isolated from three individuals ranging from age 37 to 85. RNA-seq and CITE-seq data were integrated using a weighted nearest neighbors (WNN) approach to identify 12 functionally distinct CD8+ T cell subsets. Age-related upregulation of exhaustion markers (e.g., PD-1, KLRG1) and downregulation of key effector cytokine pathways (e.g., IFN-γ, TNF-α) were subset-specific. Comparisons between rare and hyperexpanded antigen-experienced clonotypes highlighted a trade-off between cytotoxicity and long-term maintenance. Public HCMV- and public influenza-specific clonotypes were identified and exhibited similar aging-associated dysfunction. These results suggest chronic inflammation (inflammaging) compromises CD8+ T cell function regardless of antigen-specificity. We highlight the TCF7 gene as the strongest potential candidate for immune system “rejuvenation.” Our findings underscore the importance of targeted interventions to address immune decline in aging populations to improve vaccine efficacy and infectious disease outcomes in older populations.en-USPrinceton University Senior Theses