A human CD34(+) subset resides in lymph nodes and differentiates into CD56bright natural killer cells

In humans, T cells differentiate in thymus and B cells develop in bone marrow (BM), but the natural killer (NK) precursor cell(s) and site(s) of NK development are unclear. The CD56(bright) NK subset predominates in lymph nodes (LN) and produces abundant cytokines compared to the cytolytic CD56(dim) NK cell that predominates in blood. Here, we identify a novel CD34(dim) CD45RA(+) hematopoietic precursor cell (HPC) that is integrin alpha(4)beta(bright)(7). CD34(dim)CD45RA(+)beta(bright)(7) HPCs constitute < 1% of BM CD34(+) HPCs and 6% of blood CD34(+) HPCs, but > 95% of LN CD34(+) HPCs. They reside in the parafollicular T cell regions of LN with CD56(bright) NK cells, and when stimulated by IL-15, IL-2, or activated LN T cells, they become CD56(bright) NK cells. The data identify a new NK precursor and support a model of human NK development in which BM-derived CD341(dim)CD45RA(+)beta(bright)(7) HPCs reside in LN where endogenous cytokines drive their differentiation to CD56 (bright) NK cells in vivo.