Positive and negative regulation of Natural Killer cells: therapeutic implications.

Natural Killer (NK) cells can mediate numerous anti-tumor and anti-viral effector functions as well as play important immunoregulatory roles in various disease states. Promoting the ability of NK cells to respond in an immunotherapeutic setting has often been sought by the addition of NK cell-stimulating factors. However, such therapies are often found to be insufficient, which may in part be due to the presence of inhibitory influences on the NK cell. NK cells can respond to a plethora of cytokines which are generated by numerous cell types and these interactions can markedly affect NK cell survival and activity. NK cells also possess multiple activating and inhibiting receptors which can alter their function. Whether the NK cell will become activated or not can depend on a complex balance of activating and inhibitory signals received by the cell and modulation of these signals may shift the balance on NK activation. This review discusses the various activating and inhibitory stimuli which can act on NK cells, and suggests that future NK cell-based therapies consider not only activating stimuli but also removal of possible inhibitory elements which could prevent optimal NK cell function and/or survival.