CMV-specific clonal expansion of Th1, GZMK+ CD8+, and TEMRA T cells revealed by human PBMC profiling 2257482

Abstract

Abstract Introduction Cytomegalovirus (CMV) is a common herpesvirus that establishes lifelong latency and becomes increasingly prevalent with age. Methods We systematically characterized CMV-associated immune remodeling by analyzing six human cohorts (two newly built) using single-cell RNA sequencing, T cell receptor (TCR) sequencing, and flow cytometry. Results Beyond the well-known expansion of CD4+/CD8+ TEMRA, adaptive NK, and γδ T cells, CMV(+) adults exhibited increased frequencies of GZMK+ CD8+ T cells and atypical B cells, alongside a reduction of CD56dim NK cells. Longitudinal profiling of an individual who seroconverted revealed rapid CMV-driven shifts in circulating immune cell frequencies. Single-cell TCR data analyzed using a large database of CMV-associated clones combined with predictive modeling (CMVerify), identified novel CMV-specific clonal expansions reproducible across two independent cohorts. In the CD8+ lineage, CMV-specific clones were enriched in GZMK+ CD8+ and CD8+ TEMRA cells, while in the CD4+ lineage, Th1 cells showed clonal expansion alongside CD4+ TEMRA cells. Conclusion This integrative study revealed how latent CMV alters the cellular and clonal landscape, defining Th1 and GZMK+ CD8+ cells as newly recognized elements of the latent CMV response in humans. Funding Source Funding provided by the T32 Training Program in Precision Genetics of Aging, Alzheimer’s Disease and Related Dementias — (1T32AG062409-01A1) Topic Categories Computational and Systems Immunology (COMP)