As lymphocytes develop from CD34+ hematopoietic precursors they differentiate and form a highly diverse population based on variegated expression of a large number of different proteins. To what extent the gene expression in a given clonally derived mature lymphocyte is stable over several cell generations remains largely unexplored. Our recent findings indicate that CD8+ T cells maintain clonally heritable gene expression in vivo and in vitro. By using single cell RNA sequencing we were able to track clonally related human CD8+ T cells over time and analyze intra- versus interclonal gene expression patterns as well as clonally biased T cell differentiation (Mold et al, Cell Reports, 2021 and Mold et al, Biorxiv, 2022). In the current project we aim at investigating clonally heritable gene expression patterns in different human lymphocytes in vivo and in vitro, as well as tracking human lymphocyte development and differentiation at the clonal level. To this end we make use of both naturally occurring clonal expansions of lymphocytes, e.g. T cells, B cells, and adaptive-like NK cells, as well as in vitro derived clonally expanded lymphocytes. Using combinations of single cell RNAseq (10X, smartSeq3xprss) and single cell and bulk ATACseq, aim at tracking both clonally expressed receptors (T cells/B cells) as well as clonally restricted mutations in mitochondrial genes. The analyses platforms allows us to both determine which cells are clonally related and at the same time allows us to interrogate the gene expression and chromatin accessibility.