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IL-15–High-Responder Developing NK Cells Bearing Ly49 Receptors in IL-15−/− Mice

In mice lacking IL-15, NK cell development is arrested at immature stages, providing an opportunity to investigate the earliest developing NK cells that would respond to IL-15. We show in this study that immature NK cells were present in the spleen as well as bone marrow (BM) and contained IL-15–high-responder cells. Thus, mature NK cells were generated more efficiently from IL-15−/− than from control donor cells in radiation BM chimeras, and the rate of IL-15–induced cell division in vitro was higher in NK cells in the spleen and BM from IL-15−/− mice than in those from wild-type mice. Phenotypically, NK cells developed in IL-15−/− mice up to the minor but discrete CD11b–CD27+DX5hiCD51dullCD127dullCD122hi stage, which contained the majority of Ly49G2+ and D+ NK cells both in the spleen and BM. Even among wild-type splenic NK cells, IL-15–induced proliferation was most prominent in CD11b–DX5hi cells. Notably, IL-15–mediated preferential expansion (but not conversion from Ly49– cells) of Ly49+ NK cells was observed in vitro only for NK cells in the spleen. These observations indicated the uneven distribution of NK cells of different developing stages with variable IL-15 responsiveness in these lymphoid organs. Immature NK cells in the spleen may contribute, as auxiliaries to those in BM, to the mature NK cell compartment through IL-15–driven extramarrow expansion under steady-state or inflammatory conditions.