Identification of a Human Natural Killer Cell Lineage-Restricted Progenitor in Fetal and Adult Tissues

• CD34+CD38+CD123−CD45RA+CD7+CD10+CD127− cells represent NK lineage progenitor (NKP)
• NKP is located downstream of LMPP and CLP within the human hematopoietic hierarchy
• NKP generates mature functional NK cells in vitro and in vivo but no other lineages
• NKP is conserved throughout ontogeny and is found in human adult and fetal tissues

SummaryNatural killer (NK) cells are cytotoxic lymphocytes and play a vital role in controlling viral infections and cancer. In contrast to B and T lymphopoiesis where cellular and regulatory pathways have been extensively characterized, the cellular stages of early human NK cell commitment remain poorly understood. Here we demonstrate that a Lin−CD34+CD38+CD123−CD45RA+CD7+CD10+CD127− population represents a NK lineage-restricted progenitor (NKP) in fetal development, umbilical cord blood, and adult tissues. The newly identified NKP has robust NK cell potential both in vitro and in vivo, generates functionally cytotoxic NK cells, and lacks the ability to produce T cells, B cells, myeloid cells, and innate lymphoid-like cells (ILCs). Our findings identify an early step to human NK cell commitment and provide new insights into the human hematopoietic hierarchy.

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