Clonal Tracking of Rhesus Macaque Hematopoiesis Highlights a Distinct Lineage Origin for Natural Killer Cells

Analysis of hematopoietic stem cell function in nonhuman primates provides insights that are relevant for human biology and therapeutic strategies. In this study, we applied quantitative genetic barcoding to track the clonal output of transplanted autologous rhesus macaque hematopoietic stem and progenitor cells over a time period of up to 9.5 months. We found that unilineage short-term progenitors reconstituted myeloid and lymphoid lineages at 1 month but were supplanted over time by multilineage clones, initially myeloid restricted, then myeloid-B clones, and then stable myeloid-B-T multilineage, long-term repopulating clones. Surprisingly, reconstitution of the natural killer (NK) cell lineage, and particularly the major CD16+/CD56− peripheral blood NK compartment, showed limited clonal overlap with T, B, or myeloid lineages, and therefore appears to be ontologically distinct. Thus, in addition to providing insights into clonal behavior over time, our analysis suggests an unexpected paradigm for the relationship between NK cells and other hematopoietic lineages in primates. [Display omitted] •The output of individual primate HSPCs can be clonally tracked in vivo•Unilineage, bilineage, and multilineage clones can be mapped posttransplantation•Primate myeloid and B cells are more closely related than B and T cells•The dominant blood fraction of NK cells forms a unique hematopoietic lineage Quantitative tracking of rhesus macaque hematopoiesis at a single-cell level by genetic cellular barcoding highlights a distinct origin for the dominant peripheral blood natural killer cell lineage.