title: Herpes simplex virus antigens directly activate NK cells via TLR2, thus facilitating their presentation to CD4 T lymphocytes.
abstract: NK cells infiltrate human herpetic lesions, but their role has been underexplored. HSV can stimulate innate immune responses via surface TLR2, which is expressed on monocyte-derived dendritic cells (DCs) and NK cells. In this study, UV-inactivated HSV1/2 and immunodominant HSV2 glycoprotein D peptides conjugated to the TLR2 agonist dipalmitoyl-S-glyceryl cysteine stimulated CD4 T lymphocyte IFN-γ responses within PBMCs or in coculture with monocyte-derived DCs. NK cells contributed markedly to the PBMC responses. Furthermore, NK cells alone were activated directly by both Ags, also upregulating HLA-DR and HLA-DQ and then they activated autologous CD4 T lymphocytes. Using Transwells, Ag-stimulated NK cells and CD4 T lymphocytes were shown to interact through both cell-to-cell contact and cytokines, differing in relative importance in different donors. A distinct immunological synapse between Ag-stimulated NK cells and CD4 T lymphocytes was observed, indicating the significance of their cell-to-cell contact. A large proportion (57%) of NK cells was also in contact with CD4 T lymphocytes in the dermal infiltrate of human recurrent herpetic lesions. Thus, NK cells stimulated by TLR2-activating HSV Ags can present Ag alone or augment the role of DCs in vitro and perhaps in herpetic lesions or draining lymph nodes. In addition to DCs, NK cells should be considered as targets for adjuvants during HSV vaccine development.
authors.affiliation: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales 2145, Australia.
authors.forename: Min
authors.initials: M
authors.lastname: Kim
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Osborne
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zeng
authors.forename: Heather
authors.initials: H
authors.lastname: Donaghy
authors.forename: Kay
authors.initials: K
authors.lastname: McKinnon
authors.forename: David C
authors.initials: DC
authors.lastname: Jackson
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Cunningham
mesh_terms: D017951:Antigen Presentation; D000956:Antigens, Viral / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D020405:Dermis / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005260:Female; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D006558:Herpes Genitalis / Q000276:immunology / Q000378:metabolism; D022301:Herpes Simplex Virus Vaccines / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000378:metabolism; D018258:Herpesvirus 2, Human / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural; D055666:Lipopeptides / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: D000956:Antigens, Viral; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D022301:Herpes Simplex Virus Vaccines; D055666:Lipopeptides; C552442:S-(2,3-bis(palmitoyloxy)propyl)cysteine; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014759:Viral Envelope Proteins; C040570:glycoprotein D-herpes simplex virus type 2; D007371:Interferon-gamma