Claire L. Sutherland

UL16-Binding Proteins, Novel MHC Class I-Related Proteins, Bind to NKG2D and Activate Multiple Signaling Pathways in Primary NK Cells

The UL16-binding proteins (ULBPs) are a novel family of MHC class I-related molecules that were identified as targets of the human CMV glycoprotein, UL16. We have previously shown that ULBP expression renders a relatively resistant target cell sensitive to NK cytotoxicity, presumably by engaging NKG2D, an activating receptor expressed by NK and other immune effector cells. In this study we show that NKG2D is the ULBP counterstructure on primary NK cells and that its expression is up-regulated by IL-15 stimulation. Soluble forms of ULBPs induce marked protein tyrosine phosphorylation, and activation of the Janus kinase 2, STAT5, extracellular signal-regulated kinase, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signal transduction pathways. ULBP-induced activation of Akt and extracellular signal-regulated kinase and ULBP-induced IFN-γ production are blocked by inhibitors of PI 3-kinase, consistent with the known binding of PI 3-kinase to DAP10, the membrane-bound signal-transducing subunit of the NKG2D receptor. While all three ULBPs activate the same signaling pathways, ULBP3 was found to bind weakly and to induce the weakest signal. In summary, we have shown that NKG2D is the ULBP counterstructure on primary NK cells and for the first time have identified signaling pathways that are activated by NKG2D ligands. These results increase our understanding of the mechanisms by which NKG2D activates immune effector cells and may have implications for immune surveillance against pathogens and tumors.

Interaction of human cytomegalovirus glycoproteins with immunoreceptors

Summary. The use of glycoproteins encoded by human cytomegalovirus as probes to isolate their cellular counterstructures has resulted in the discovery of novel immunoreceptors. The HCMV -encoded MHC class I homolog, ULl8, binds to LlR-I /ILT2, an inhibitory signaling receptor for cellular MHC class I antigens with a broad distribution on leukocytes, including some NK cells. Although ULl8 has been proposed to act as an inhibitor of NK cytotoxicity, this remains controversial. Another HCMV-encoded glycoprotein, ULl6, binds to members of a novel non-classical MHC class l-related family , the ULBPs, as well as to MICB, a known non-cla ssical MHC class I antigen . The MIC s and ULBPs are ligands for the activating receptor, NKG2DIDAPI0, expressed by NK and other immune effector cells. Ligation of NKG2DIDAPI 0 by ULBPs or MICs on a target cell can overcome an inhibitory signal mediated by NK recogn ition of MHC class I antigens and allow NK cytotoxicity. UL 16 masking of ULBP or MIC recognition may represent a mechani sm of immune evasion by CMV .