Tri-modal Single Cell Approach Reveals Cellular and Molecular Heterogeneity in Naïve T cells Across Human Age

The naïve T cell compartment undergoes multiple changes across age that associate with altered susceptibility to infection and autoimmunity. In addition to the acquisition of naïve-like memory T cell subsets, recent murine studies describe substantial molecular reprogramming of the naïve compartment in adults compared with adolescents. However, these alterations are not well delineated in human aging. Using a new trimodal single cell technology (TEA-seq), we discovered that the composition as well as the transcriptional and epigenetic programming of the naïve T cell compartment in children (11-13 yrs) is distinct from that of older adults (55-65 yrs). Naive CD4 T cells, previously considered relatively resistant to aging, exhibited far more pronounced molecular reprogramming than the CD8 compartment, in which alterations are preferentially driven by shifts in naive-like memory subsets. These data reveal the complex nature of the naïve T cell compartment that may contribute to differential immune responses across the spectrum of human age. scRNAseq was performed on 48 samples. In addition, TEA-seq (a novel method for simulaneous single-cell profiling of transcripts, epitopes, and chromatin accessiblity) was performed on 16 of those samples, as well as on 3 control samples (IMM19_435, IMM19_438, and IMM19_445). As part of TEA-seq testing we prepared CITE-seq, scATAC-seq, single-cell and single-nuclei 10x Multiome ATAC + Gene Expression, and TEA-seq libraries from the same PBMC sample in parallel. **The submitter declares that the raw data are being deposited in dbGaP due to patient privacy concerns.**