title: Modulation of NKp30- and NKp46-mediated natural killer cell responses by poxviral hemagglutinin.
abstract: Natural killer (NK) cells are an important element in the immune defense against the orthopox family members vaccinia virus (VV) and ectromelia virus (ECTV). NK cells are regulated through inhibitory and activating signaling receptors, the latter involving NKG2D and the natural cytotoxicity receptors (NCR), NKp46, NKp44 and NKp30. Here we report that VV infection results in an upregulation of ligand structures for NKp30 and NKp46 on infected cells, whereas the binding of NKp44 and NKG2D was not significantly affected. Likewise, infection with ectromelia virus (ECTV), the mousepox agent, enhanced binding of NKp30 and, to a lesser extent, NKp46. The hemagglutinin (HA) molecules from VV and ECTV, which are known virulence factors, were identified as novel ligands for NKp30 and NKp46. Using NK cells with selectively silenced NCR expression and NCR-CD3ζ reporter cells, we observed that HA present on the surface of VV-infected cells, or in the form of recombinant soluble protein, was able to block NKp30-triggered activation, whereas it stimulated the activation through NKp46. The net effect of this complex influence on NK cell activity resulted in a decreased NK lysis susceptibility of infected cells at late time points of VV infection when HA was expression was pronounced. We conclude that poxviral HA represents a conserved ligand of NCR, exerting a novel immune escape mechanism through its blocking effect on NKp30-mediated activation at a late stage of infection.
authors: Translational Immunology Research Unit, German Cancer Research Center, Heidelberg, Germany.
authors: Mostafa
authors: M
authors: Jarahian
authors: Manuela
authors: M
authors: Fiedler
authors: André
authors: A
authors: Cohnen
authors: Dominik
authors: D
authors: Djandji
authors: Günter J
authors: GJ
authors: Hämmerling
authors: Cornelius
authors: C
authors: Gati
authors: Adelheid
authors: A
authors: Cerwenka
authors: Peter C
authors: PC
authors: Turner
authors: Richard W
authors: RW
authors: Moyer
authors: Carsten
authors: C
authors: Watzl
authors: Hartmut
authors: H
authors: Hengel
authors: Frank
authors: F
authors: Momburg
mesh_terms: D000818:Animals; D002460:Cell Line; D004481:Ectromelia virus / Q000276:immunology*; D015967:Gene Expression Regulation, Viral; D006388:Hemagglutinins / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000378:metabolism*; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014616:Vaccinia virus / Q000276:immunology*
chemical_list: D006388:Hemagglutinins; C112260:NCR1 protein, human; C431710:NCR3 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins