Activating NK Cell Receptors Providing Immunity Against Viruses and Tumors

NK cells use activating receptors employing three biochemically distinct pathways in order to provide innate immunity against tumors and pathogens. Similar to the B- and T-cell receptors, several NK cell receptors, including the activating KIR and Ly49 receptors, signal by association with the ITAM-bearing adapter protein DAP12. Ly49H has been implicated directly in viral recognition. ITAM-based signaling requires the Syk and ZAP70 kinases and the involvement of this pathway in tumor killing is under study. A second pathway of NK activation involves PI3 kinase. DAP10 adapter protein activates this pathway and permits NK cells to kill tumors bearing ligands of the DAP10-associated NKG2D receptor. Studies using neutralizing anti-NKG2D mAb in vivo implicate this receptor in both anti-tumor and anti-viral functions. An independent pathway of activation which amplifies these responses involves the SAP adaptor protein linked to the CD244 (2B4) NK receptors. Full NK activation requires a synergy between the PI3 kinase, Syk/ZAP70 and SAP pathways to permit optimal attach against cancer.