UL16 Binding Protein 4 (ULBP4), also known as RAET1E, is a member of the UL16-binding protein family. These proteins are ligands for the NKG2D receptor, which is an activating receptor found on natural killer (NK) cells, CD8+ T cells, and γδ T cells. ULBP4 plays a crucial role in immune surveillance, particularly in the context of tumor immunity and viral infections.
ULBP4 is expressed on the surface of various human tumor cells, including ovarian epithelial carcinoma and colonic carcinoma cells . It is also found on Epstein-Barr virus (EBV)-infected peripheral blood cells . The expression of ULBP4 can be induced by cellular stress, infection, and transformation, making it a marker for abnormal cells.
ULBP4 functions as a ligand for both the NKG2D receptor and the TCRγδ receptor. When ULBP4 binds to these receptors, it activates NK cells and γδ T cells, leading to the secretion of Th1 cytokines and the induction of cytotoxicity against target cells . This dual recognition by NKG2D and TCRγδ enhances the immune response against tumors and infected cells.
The binding of ULBP4 to the NKG2D receptor on NK cells and T cells triggers a signaling cascade that results in the activation and proliferation of these immune cells. This interaction enhances the cytotoxic activity of NK cells and γδ T cells, leading to the destruction of target cells expressing ULBP4 . Additionally, soluble forms of ULBP4 can down-regulate the surface expression of NKG2D, modulating the immune response .
The expression of ULBP4 is regulated by various factors, including cellular stress, infection, and transformation. The presence of ULBP4 on the cell surface can be modulated by viral proteins, such as the human cytomegalovirus-encoded UL16, which selectively binds to certain NKG2D ligands . This interaction can influence the immune response by altering the availability of ULBP4 for recognition by immune cells.
Human recombinant ULBP4 is produced using recombinant DNA technology, which involves the insertion of the ULBP4 gene into an expression vector and its subsequent expression in a suitable host cell system. Recombinant ULBP4 is used in research to study its interactions with NKG2D and TCRγδ receptors, as well as its role in immune surveillance and tumor immunity.