A four-stage model for murine natural killer cell development in vivo

Natural killer (NK) cells are the predominant innate lymphoid cells that mediate anti-viral and anti-tumor immunity. NK cells arise from hematopoietic stem cells in the bone marrow (BM) and undergo lineage specification and maturation. Despite the importance of NK cells for innate immunity and the development of innovative cancer therapy, the detailed steps linking NK progenitor (NKP) cell development through immature NK (iNK) cells to mature NK (mNK) cells are poorly defined. In this study, we found that CD49b, NK1.1, and NKp46 are sequentially acquired during the development of murine Lin⁻CD122⁺ NKP cells. Introducing NKp46 allows us to propose a four-stage developmental model, wherein CD122⁺NK1.1⁻CD49b⁻NKp46⁻ defines an NKP population, CD122⁺NK1.1⁻CD49b⁺NKp46⁻ and CD122⁺NK1.1⁺CD49b^−/+ NKp46⁻ define iNK-a and iNK-b populations, respectively, and CD122⁺NK1.1⁺CD49b⁺NKp46⁺ defines an mNK population. These four NK cell populations are phenotypically distinct based on their expression of cell surface markers, transcription factors, and effector molecules. Using a differentiation assay ex vivo and adoptive transfer model in vivo, we confirmed that NK cell development follows our predicted four-stage model. Taken together, our findings establish two distinct populations of immature NK cells and define a model for mouse NK cell development.