A potential role for RAG-1 in NK cell development revealed by analysis of NK cells during ontogeny

Little is known regarding natural killer (NK) cell development in hematopoietic and visceral organs during ontogeny. We sought to determine NK cell accumulation during ontogeny and whether organ-specific niches altered development. Neonatal NK cells in the bone marrow, spleen and lung exist as immature CD27(+)/CD11B(lo) cells. The first appearance of mature CD27(lo)/CD11B(+) cells occurs at 3 weeks of age whereas maturation is complete by 8 weeks. In contrast, maturation of liver NK cells is essentially finished at 2 weeks. A role for RAG-1 (recombination-activating gene-1 product) in NK cell development was suggested as RAG-1-deficient mice accumulated NK cells differently. Surprisingly, bone marrow and spleen NK cells are absent in neonatal RAG-1(-/-) mice and an overrepresentation of a precursor NK cell subset, found normally in the liver, was observed in the bone marrow of RAG-1(-/-) mice. As mice lacking specific adaptive immune elements, including T and/or B cells, have normal NK cell repertoires, a more direct role for RAG during NK cell development cannot be excluded. Liver NK cells may represent an independent pool of cells from those developing out of the bone marrow, and RAG-1 itself may have a significant role in NK cell development.