Dissecting human NK cell development and differentiation

Our understanding of human NK cell biology lags behind that of the mouse NK cell biology; this is in a large part because of the ethical and logistical restrictions to the access of healthy human lymphoid tissue and the experimental manipulation in vivo. Nevertheless, in-depth analyses in genetically modified mice have provided us with models for NK cell development, differentiation, and function that guide our thinking about the role of NK cells in immune defense. Collectively, mouse and human studies have unveiled a number of conserved transcription factors, cytokines, cell surface receptors, and associated signaling proteins that are essential for normal NK cell development. Still, human and mouse NK cells differ with regard to expression of several key cell surface receptors, kinetics of development, and frequency in adult lymphoid organs (Huntington ND, Vosshenrich CA, Di Santo JP. Nat Rev Immunol 7:703-714, 2007). Accordingly, the specific biological roles for NK cells in human immune responses remain poorly described. New preclinical animal models that allow the analysis of human immune system development in function may provide a means to further our understanding of the biology of human NK cells in vivo.