Self-tolerance of natural killer cells

Natural killer (NK) cells are lymphocytes of the innate immune system. They are significant producers of cytokines such as interferon-γ and can lyse tumour cells, virus-infected cells and transplanted bone-marrow allografts.Similar to other lymphocytes, NK cells achieve tolerance to self. This means that although they can attack self cells, there are specific developmental mechanisms that ensure that this does not normally occur.Recognition and lysis of target cells by NK cells is regulated by the interplay of many stimulatory and inhibitory receptors.Many NK cells are prevented from attacking self cells through the expression of inhibitory receptors specific for self MHC class I molecules. However, recent data strongly indicate that not all NK cells express an inhibitory receptor for self MHC class I molecules.NK cells that fail to express an inhibitory receptor specific for a self MHC class I molecule are hyporesponsive to stimuli provided by self cells. However, the hyporesponsiveness seems to be contextual, because the hyporesponsive population of NK cells can nevertheless mount normal responses to other stimuli, such as cells infected with Listeria monocytogenes.Several mechanisms to account for the tolerance of NK cells have been proposed recently, including an 'arming' model and a 'disarming' model. This Review considers the evidence for and against these models.