IL-15: A seemingly indispensable factor for bone marrow-derived NK cell maturation

The role of NK cells in the immune response has been extensively studied. However, the ontogeny and development of NK cells still remains largely undefined. Mice that lack either the common γ or the IL-2/IL-15R β chain are devoid of functional NK cells. In contrast, IL-2 and IL-2Rα KO mice have NK cells, an observation supporting a role for IL-15 in NK cell development. Thus we postulated that IL-15 deficiency may result in the loss of NK cells. Indeed, we demonstrate here that mice lacking the expression of the interferon regulatory factor(IRF)-1 have a deficiency in NK cells associated with the loss of IL-15 expression in the bone marrow (BM) microenvironment. IL-15 restored NK cell development/function in the IRF-1 ^-/- BM, indicating that IL-15 acts to induce NK development from intact progenitor cells. Addition of IL-15 to normal BM cells yielded an almost pure population of NK1.1 ⁺/CD3 ^- cells that exhibit potent lytic activity against the YAC-1 cells. Unlike most peripheral NK cells, the BM-derived NK1.1 ⁺/CD3 ^- cells induced by IL-15 homogenously expressed CD117 (c-kit), the receptor for stem cell factor (SCF). These IL-15 induced CD117 ⁺/NK1.1 ⁺/CD3 ^- cells proliferated in response to SCF alone. Furthermore, we observed a reduced ability of IL-15 to induce NK differentiation from BM cells of Sl/Sl ^d mice that lack SCF. Collectively, these results indicate that IL-15 is the primary factor involved in NK cell maturation and function, and that SCF acts as a co-factor by stimulating progenitors and differentiated NK cells during development.