Epigenomics of human CD8 T cell differentiation and aging

The efficacy of the adaptive immune response declines markedly with age, but the cell-intrinsic mechanisms driving immune aging in humans remain poorly understood. Immune aging is characterized by a loss of self-renewing naive cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using the assay for transposase-accessible chromatin using sequencing, we inferred that the transcription factor binding activities correlated with naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA sequencing, we identified transcription networks associated with CD8 T cell differentiation, with prominent roles implicated for BATF, ETS1, Eomes, and Sp1. Extending our analysis to aged humans, we found that the differences between the memory and naive CD8 T cell subsets were largely preserved across age but that naive and central memory cells from older individuals exhibited a shift toward more differentiated patterns of chromatin openness. In addition, aged naive cells displayed a loss in chromatin accessibility at gene promoters, largely associated with a decrease in nuclear respiratory factor 1 (NRF1) binding. This shift was implicated in a marked drop-off in the ability of the aged naive cells to transcribe respiratory chain genes, which may explain the reduced capacity of oxidative phosphorylation in older naive cells. Our findings identify BATF- and NRF1-driven gene regulation as potential targets for delaying CD8 T cell aging and restoring function.