Dissecting NK Cell Development Using a Novel Alymphoid Mouse Model: Investigating the Role of the C-abl Proto-oncogene in Murine NK Cell Differentiation

NK lymphocytes participate in both innate and adaptive immunity by their prompt secretion of cytokines including IFN-gamma, which activates macrophages, and by their ability to lyse virally infected cells and tumor cells without prior sensitization. Although these characteristics of NK cells are well documented, little is known about the genetic program that orchestrates NK development or about the signaling pathways that trigger NK effector functions. By crossing NK-deficient common gamma-chain (gammac) and recombinase activating gene (RAG)-2 mutant mice, we have generated a novel alymphoid (B-, T-, and NK-) mouse strain (RAG2/gammac) suitable for NK complementation in vivo. The role of the c-abl proto-oncogene in murine NK cell differentiation has been addressed in hemopoietic chimeras generated using RAG2/gammac mice reconstituted with c-abl-/- fetal liver cells. The phenotypically mature NK cells that developed in the absence of c-abl were capable of lysing tumor targets, recognizing "missing self," and performing Ab-dependent cellular cytotoxicity. Taken together, these results exclude any essential role for c-abl in murine NK cell differentiation in vivo. The RAG2/gammac model thereby provides a novel approach to establish a genetic map of NK cell development.