NK cells are innate lymphocytes that bridge innate and adaptive immunity. They directly defend against pathogens through cytotoxicity and cytokine production and indirectly by regulating antigen-presenting cells and T cell responses. Unlike B and T cells, NK cells lack receptor diversity from DNA rearrangement but share some adaptive immune properties. They can distinguish between healthy and diseased cells, mount strong antiviral responses, and maintain long-lived cells. A key question is how NK cells achieve specificity in their responses and avoid attacking healthy cells. Recent studies have revealed that NK cell responses are regulated by a complex network of signals from various receptors. Activation requires synergistic signals from multiple receptors, while inhibitory receptors for MHC-I play a critical role in controlling responses and maintaining responsiveness. These receptors block activation signals and trigger phosphorylation of the small adaptor Crk, leading to a "revocable license" model for NK cell responsiveness. Inhibitory receptors for MHC-I also confer intrinsic responsiveness, a process called "licensing." This licensing is ITIM-dependent and requires the presence of an MHC-I ligand. NK cell responsiveness can be tuned up or down through adaptation to the MHC-I environment. Inhibitory receptors also transmit signals other than tyrosine phosphatase-dependent dephosphorylation. NK cells are regulated by soluble factors, including chemokines, cytokines, and secreted ligands. They contribute to infection control, tumor immunosurveillance, and homeostasis in the lymphoid system. They also play a role in reproduction by interacting with fetal trophoblast cells and remodeling maternal vasculature. NK cell activation requires synergistic combinations of receptors, as no single receptor is sufficient. For example, CD16 can activate degranulation on its own, while other receptors like NKp46 require synergy with other receptors. The synergy between receptors is essential to prevent unrestrained activation. The signaling pathways of NK cell receptors are complex, involving multiple intermediate steps. For example, granule polarization and degranulation are controlled by different activation pathways. The integration of signals at the immunological synapse is crucial for NK cell function. The β2 integrin LFA-1 plays a central role in NK cell signaling, as it can signal autonomously and is involved in granule polarization and adhesion. Soluble factors like IL-15 and type I IFN also regulate NK cell function. IL-15 is trans-presented by cells expressing the IL-15Rα-IL-15 complex, while type I IFN receptors signal through Stat1 and Stat2 to induce a cytolytic program. NK cells also express Stat4, which signals for IFN-γ secretion in response to type I IFN. Sphingosine-1-phosphate (S1P) is important for NK cell migration, as they rely on S1PR5, which is not subject to ligand-dependent desensNK cells are innate lymphocytes that bridge innate and adaptive immunity. They directly defend against pathogens through cytotoxicity and cytokine production and indirectly by regulating antigen-presenting cells and T cell responses. Unlike B and T cells, NK cells lack receptor diversity from DNA rearrangement but share some adaptive immune properties. They can distinguish between healthy and diseased cells, mount strong antiviral responses, and maintain long-lived cells. A key question is how NK cells achieve specificity in their responses and avoid attacking healthy cells. Recent studies have revealed that NK cell responses are regulated by a complex network of signals from various receptors. Activation requires synergistic signals from multiple receptors, while inhibitory receptors for MHC-I play a critical role in controlling responses and maintaining responsiveness. These receptors block activation signals and trigger phosphorylation of the small adaptor Crk, leading to a "revocable license" model for NK cell responsiveness. Inhibitory receptors for MHC-I also confer intrinsic responsiveness, a process called "licensing." This licensing is ITIM-dependent and requires the presence of an MHC-I ligand. NK cell responsiveness can be tuned up or down through adaptation to the MHC-I environment. Inhibitory receptors also transmit signals other than tyrosine phosphatase-dependent dephosphorylation. NK cells are regulated by soluble factors, including chemokines, cytokines, and secreted ligands. They contribute to infection control, tumor immunosurveillance, and homeostasis in the lymphoid system. They also play a role in reproduction by interacting with fetal trophoblast cells and remodeling maternal vasculature. NK cell activation requires synergistic combinations of receptors, as no single receptor is sufficient. For example, CD16 can activate degranulation on its own, while other receptors like NKp46 require synergy with other receptors. The synergy between receptors is essential to prevent unrestrained activation. The signaling pathways of NK cell receptors are complex, involving multiple intermediate steps. For example, granule polarization and degranulation are controlled by different activation pathways. The integration of signals at the immunological synapse is crucial for NK cell function. The β2 integrin LFA-1 plays a central role in NK cell signaling, as it can signal autonomously and is involved in granule polarization and adhesion. Soluble factors like IL-15 and type I IFN also regulate NK cell function. IL-15 is trans-presented by cells expressing the IL-15Rα-IL-15 complex, while type I IFN receptors signal through Stat1 and Stat2 to induce a cytolytic program. NK cells also express Stat4, which signals for IFN-γ secretion in response to type I IFN. Sphingosine-1-phosphate (S1P) is important for NK cell migration, as they rely on S1PR5, which is not subject to ligand-dependent desens