title: HSV-2 specifically down regulates HLA-C expression to render HSV-2-infected DCs susceptible to NK cell killing.
abstract: Both NK cells and CTLs kill virus-infected and tumor cells. However, the ways by which these killer cells recognize the infected or the tumorigenic cells are different, in fact almost opposite. CTLs are activated through the interaction of the TCR with MHC class I proteins. In contrast, NK cells are inhibited by MHC class I molecules. The inhibitory NK receptors recognize mainly MHC class I proteins and in this regard practically all of the HLA-C proteins are recognized by inhibitory NK cell receptors, while only certain HLA-A and HLA-B proteins interact with these receptors. Sophisticated viruses developed mechanisms to avoid the attack of both NK cells and CTLs through, for example, down regulation of HLA-A and HLA-B molecules to avoid CTL recognition, leaving HLA-C proteins on the cell surface to inhibit NK cell response. Here we provide the first example of a virus that through specific down regulation of HLA-C, harness the NK cells for its own benefit. We initially demonstrated that none of the tested HSV-2 derived microRNAs affect NK cell activity. Then we show that surprisingly upon HSV-2 infection, HLA-C proteins are specifically down regulated, rendering the infected cells susceptible to NK cell attack. We identified a motif in the tail of HLA-C that is responsible for the HSV-2-meduiated HLA-C down regulation and we show that the HLA-C down regulation is mediated by the viral protein ICP47. Finally we show that HLA-C proteins are down regulated from the surface of HSV-2 infected dendritic cells (DCs) and that this leads to the killing of DC by NK cells. Thus, we propose that HSV-2 had developed this unique and surprising NK cell-mediated killing strategy of infected DC to prevent the activation of the adaptive immunity.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel-Canada of Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Elboim
authors.forename: Inna
authors.initials: I
authors.lastname: Grodzovski
authors.forename: Esther
authors.initials: E
authors.lastname: Djian
authors.forename: Dana G
authors.initials: DG
authors.lastname: Wolf
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
mesh_terms: D056704:Adaptive Immunity; D002470:Cell Survival; D003001:Cloning, Molecular; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D015236:HLA-C Antigens / Q000378:metabolism*; D006566:Herpesviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology
chemical_list: D015236:HLA-C Antigens; C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins
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