Clonal expansion and compartmentalized maintenance of rhesus macaque NK cell subsets

Natural killer (NK) cells recognize and eliminate infected and malignant cells. Their life histories are poorly understood, particularly in humans, due to lack of informative models and endogenous clonal markers. Here, we apply transplantation of barcoded rhesus macaque hematopoietic cells to interrogate the landscape of NK cell production, expansion, and life histories at a clonal level long term and after proliferative challenge. We identify oligoclonal populations of rhesus CD56^-CD16⁺ NK cells that are characterized by marked expansions and contractions over time yet remained long-term clonally uncoupled from other hematopoietic lineages, including CD56⁺CD16^- NK cells. Individual or groups of CD56^-CD16⁺ expanded clones segregated with surface expression of specific killer immunoglobulin-like receptors. These clonally distinct NK cell subpopulation patterns persisted for more than 4 years, including after transient in vivo anti-CD16-mediated depletion and subsequent regeneration. Profound and sustained interleukin-15-mediated depletion was required to generate new oligoclonal CD56^-CD16⁺ NK cells. Together, our results indicate that linear NK cell production from multipotent hematopoietic progenitors or less mature CD56⁺CD16^- cells is negligible during homeostasis and moderate proliferative stress. In such settings, peripheral compartmentalized self-renewal can maintain the composition of distinct, differentiated NK cell subpopulations.