Tri-modal single cell profiling reveals a distinct pediatric CD8αα T cell subset and broad age-related molecular reprogramming across the T cell compartment

Age-associated changes in the T cell compartment are well-described. However, limitations of current single- or bi-modal single-cell assays, including flow cytometry, RNA-seq, and CITE-seq, have restricted our ability to deconvolve more complex cellular and molecular changes. Here, we profile more than 300,000 single T cells from healthy children (11–13 yrs) and older adults (55–65 yrs) using the trimodal assay, TEA-seq (protein, RNA, and chromatin accessibility), revealing that molecular programming of T cell subsets shifts toward a more activated basal state with age. Naive CD4 T cells, considered relatively resistant to aging, exhibited pronounced transcriptional and epigenetic reprogramming. Moreover, we discovered a novel CD8aa T cell subset lost with age that is epigenetically poised for rapid effector responses and displays distinct inhibitory, co-stimulatory and tissue homing properties. Together, these data reveal new insights into age-associated changes in the T cell compartment that may contribute to differential immune responses.