The UL16-binding proteins, a novel family of MHC class I-related ligands for NKG2D, activate natural killer cell functions

The UL16-binding proteins (ULBPs) are a novel family of MHC class I-related molecules (MICs) that were identified based on their ability to bind to th e human cytomegalovirus (HCM-V) glycoprotein UL16. UL16 also binds to a mem ber of another family of MHC class I-like molecules, MICB. The ULBPs and MI Cs are ligands for NKG2D/DAP10, an activating receptor expressed by natural killer (NK) cells and other immune effector cells, and this interaction ca n be blocked by UL16. Engagement of NKG2D/DAP10 by ULBPs or MICs expressed on a target cell can overcome an inhibitory signal generated by NK-cell rec ognition of MHC class I molecules and trigger NK cytotoxicity ULBPs elicit their effects on NK cells by activating the janus kinase 2, signal transduc er and activator of transcription 5, extracellular-signal-regulated kinase mitogen-activated protein kinase and Akt/protein kinase B signal transducti on pathways. Although ULBPs alone activate multiple signaling pathways and induce modest cytokine production, ULBPs synergize strongly with interleuki n-12 for production of interferon-gamma by NK cells. This finding is consis tent with reports in T cells that NKG2D/DAP10 can act as a costimulatory re ceptor in a similar maimer as CD28. The possible roles of ULBPs in mediatin g immune responses to viruses and tumors and the potential mechanisms by wh ich UL16 may allow HCMV to evade immune detection are areas of active inves tigation.