Multidimensional profiling of human T cells reveals high CD38 expression marking recent thymic emigrants and age-related naive T cell remodeling 2488

Abstract Description Thymic involution is a major driver of immune aging, leading to reduced thymic output and a decline in recent thymic emigrant (RTE) naive T cells in circulation. This decline may compromise immune responsiveness, which is essential for protection against infections, effective vaccination, and cancer immunosurveillance in older adults. However, the precise definition of human RTEs and their associated markers has been lacking to date. Using systems immunology approaches, including scRNA/ATAC-seq, we identified RTEs by the expression of key transcription factors SOX4, IKZF2, and TOX, and confirmed that high CD38 surface expression reliably marks both CD8 and CD4 RTEs. We then examined the dynamics of RTEs and mature cells in a cohort of 158 individuals, including age-altered cytokine production profiles and transcriptional reprogramming. Spectral cytometry further demonstrated two shared axes of T cell aging within naive CD8 and CD4 populations: (1) a progressive decrease in CD38 ++ cells (RTEs) and (2) an increase in CXCR3hi cells. These findings underscore a critical shift in naive T cell composition, reflecting broader immune remodeling with age. Identifying RTEs offers a direct measure of thymic health, providing a valuable biomarker for tracking thymic output over time. This characterization of naive T cell remodeling offers important insights into age-related immune decline, which may contribute to weaker vaccine responses and increased cancer risk in older adults. Funding Sources Supported by the Aging Biology Foundation grant to M.N.A. Topic Categories Computational and Systems Immunology (COMP)