However, the authors did not confirm the expression of TLR2 on NK cells, or whether the activation of NK cells by HSV1 was mediated by the TLR2-gB interaction (20)
However, the authors did not confirm the expression of TLR2 on NK cells, or whether the activation of NK cells by HSV1 was mediated by the TLR2-gB interaction (20). NK cells called Fc-bridged cell-mediated cytotoxicity. studies have confirmed that expression of ICP47 decreases surface MHC I on HSV1-infected human cells and consequently activates NK cells in co-culture (12, 34). However, ICP47 binds murine TAP1/2 poorly (30) and does not efficiently block traffic of mouse MHC I (35), making it difficult to test whether the downregulation of MHC I could affect NK cell activation and clearance of HSV1 contamination remains unresolved and awaits better models to resolve this issue. NKG2D Ligands NKG2D is one of the major NK cell receptors involved in recognition and killing of tumor cells and virus-infected cells (38). In humans, NKG2D is usually engaged by several ligands, namely MHC class I polypeptide-related sequence A and B (MICA and MICB) and the UL16-binding proteins 1C6 (ULBP1C6) (39). It has been reported that an HSV1-infected cell line had lower expression of MICA and ULBP2, which could potentially help HSV1-infected cells to evade recognition by NK cells (40, 41). Although the exact mechanism for this downregulation of MICA and ULBP2 is usually unknown, the recycling of membrane protein and general inhibition of synthesis of cellular proteins during HSV1 contamination might contribute to the decrease of NKG2D ligand expression (29). NK cells from patients with active HSV1 contamination had a higher level of NKG2D (40), possibly induced by an elevated Rabbit polyclonal to ADI1 level of type I IFN during HSV1 contamination (42). The increased NKG2D levels may sensitize NK cells and counteract the effect of decreased NKG2D Pradefovir mesylate ligand expression on HSV1-infected cells. Glycoprotein D Pierre Lebon reported that diploid cells infected with HSV1 can induce IFN production by peripheral blood mononuclear cells, and that HSV1 gD was responsible for this biological effect (23). HSV1 gD, encoded by the Us6 gene, is the major glycoprotein mediating entry of HSV1 into host cells. It binds two cellular receptors: herpesvirus entry mediator (HVEM) and nectin1 (43). While nectin1 has not been identified to have any regulatory function, HVEM is usually a member of the tumor necrosis factor alpha superfamily and plays very diverse functions in modulating T-cell function by activating both inflammatory and inhibitory signaling pathways (44). Herpesvirus entry mediator binds many functionally diverse cellular proteins, including LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes), lymphotoxin-, B and T lymphocyte attenuator (BTLA), and CD160. Crystal structure of the HVEM-ligand complex shows that the binding sites on HVEM for gD, BTLA, and CD160 are overlapping or very close (45). HVEM is usually ubiquitously expressed by both human and mouse immune cells (our unpublished Pradefovir mesylate data). A recent study showed that HVEM was required for IFN production following contamination in mice (46). Collectively, these results suggest that HVEM might not only be the entry mediator, but also the immune sensor for HSV1 contamination. However, we recently reported that expression of gD makes glioma resistant to NK cell cytotoxicity (47), as well as others reported that blocking gD did not affect the response of NK cells to HSV1-infected cells (20, 27, 28). Thus, the role of gD in NK cell response to HSV1 contamination is usually yet to be clarified, similar to the role of HVEM in this process. Glycoprotein B Herpes simplex virus type 1 gB promotes viral attachment through conversation with cell surface heparin sulfate (48), and also plays an essential role in mediating membrane fusion (49). HSV1 gB has been reported as having a role in the NK cell lysis of HSV1-infected endothelial cells (24C26). A lower lysis of target cells infected with HSV1 was observed when viruses were deficient in gB, or when Fab fragments of a gB-specific antibody were added to block gB (24C26). Leoni et al. reported that gB was able to physically interact with toll-like receptor-2 (TLR2) (27). In another study, Kim et al. reported that this activation of NK cells by UV-inactivated HSV1 virions was directly mediated Pradefovir mesylate by TLR2 (20). They showed that UV-inactivated HSV1 virions could bind the endothelial cell line HEK when ectopically expressing TLR2, but not native HEK2 cells that lack TLR2. However, the authors did not confirm the expression of TLR2 on NK cells, or whether the activation of NK cells by HSV1 was mediated by the TLR2-gB conversation (20). The.