Transcript-indexed ATAC-seq reveals paired single-cell T cell receptor identity and chromatin accessibility for precision immune profiling [single cell]

T cells create vast amounts of diversity in their T cell receptor (TCR) genes, enabling individual clones to recognize particular peptide-MHC ligands. Here we combine transposase accessible chromatin analysis and TCR sequencing (T-ATAC-seq) at the single-cell level. Using this approach, we identify epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers, and primary leukemic T cells from clinical patient samples. In healthy peripheral blood CD4+ T cells, we identify cis and trans regulators of naive and memory T cell states and find significant heterogeneity in surface marker-defined populations. In patients with cutaneous T cell lymphoma, we identify leukemic and non-leukemic regulatory pathways in cells from the same individual, which has been previously challenging. Thus, T-ATAC-seq is a new tool enabling analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity, and immunotherapy. Overall design: CD4+ Jurkat cells, primary CD4+ T cell subsets sorted from peripheral blood of healthy human volunteers, or primary CD4+ T cells sorted from peripheral blood of patients with Sezary syndrome. Single cells from each cell population were subjected to open chromatin single-cell ATAC-seq profiling. Single-cell samples include Jurkat cells, CD4+ Naive T cells, CD4+CD45RA- Memory T cells, CD4+ TH17 cells, and CD26+ and CD26- CD4+ cells from Sezary patients. Single cell experiments were performed in cell samples from 2-3 biological replicates (each replicate is indicated by it''s J or C plate number).