Transcript-indexed ATAC-seq for precision immune profiling

T cells create vast amounts of diversity in their T cell receptor (TCR) genes, enabling individual clones to recognize specific peptide-MHC ligands. Here we combine TCR sequencing and assay for transposase-accessible chromatin analysis at the single-cell level to provide information on the TCR specificity and epigenomic state of individual T cells. Using this approach, termed Transcript-indexed ATAC-seq (T-ATAC-seq), we identify epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers, and primary leukemic T cells from patient samples. In healthy peripheral blood CD4(+) T cells, we identify cis and trans regulators of naive and memory T cell states and find substantial heterogeneity in surface marker-defined T cell populations. In patients with cutaneous T cell lymphoma, T-ATAC-seq enabled identification of leukemic and non-leukemic regulatory pathways in T cells from the same individual, separating signals arising from the malignant clone from background T cell noise. Thus, T-ATAC-seq is a new tool that enables analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity, and immunotherapy.