Epigenetic quantification of immunosenescent CD8⁺ TEMRA cells in human blood

Age-related changes in human T-cell populations are important contributors to immunosenescence. In particular, terminally differentiated CD8⁺ effector memory CD45RA⁺ TEMRA cells and their subsets have characteristics of cellular senescence, accumulate in older individuals, and are increased in age-related chronic inflammatory diseases. In a detailed T-cell profiling among individuals over 65 years of age, we found a high interindividual variation among CD8⁺ TEMRA populations. CD8⁺ TEMRA proportions correlated positively with cytomegalovirus (CMV) antibody levels, however, not with the chronological age. In the analysis of over 90 inflammation proteins, we identified plasma TRANCE/RANKL levels to associate with several differentiated T-cell populations, including CD8⁺ TEMRA and its CD28^- subsets. Given the strong potential of CD8⁺ TEMRA cells as a biomarker for immunosenescence, we used deep-amplicon bisulfite sequencing to match their frequencies in flow cytometry with CpG site methylation levels and developed a computational model to predict CD8⁺ TEMRA cell proportions from whole blood genomic DNA. Our findings confirm the association of CD8⁺ TEMRA and its subsets with CMV infection and provide a novel tool for their high throughput epigenetic quantification as a biomarker of immunosenescence.