title: Monophosphoryl lipid A and QS21 increase CD8 T lymphocyte cytotoxicity to herpes simplex virus-2 infected cell proteins 4 and 27 through IFN-gamma and IL-12 production.
abstract: We have shown previously that IFN-gamma pretreatment of human epidermal cells (ECs) cultured in vitro partially reverses down-regulation of surface MHC class I by HSV infection, allowing recognition by CD8 CTLs, and that HSV immediate early (IE)/early (E) proteins are the predominant targets for CD8 CTLs. In this study of 25 subjects, CD8 CTLs recognized the HSV-2 IE infected cell protein 27 (ICP27) (expressed in autologous IFN-gamma-pretreated, Vaccinia virus recombinant-infected ECs) in all subjects studied, ICP4 in 89%, and ICP0 in 11%. The main hierarchy of recognition was ICP27 > ICP4. ICP27 was the dominant target in 89% of subjects but showed great individual variability in the degree of cytotoxicity. CD8 cytotoxicity specific for HSV-2 IE proteins was enhanced by 48-67% when CD8 CTLs were coincubated with the combination of monophosphoryl lipid A and QS21 adjuvants at the time of Ag presentation. These adjuvants also significantly enhanced IL-12 and IFN-gamma production from nonadherent mononuclear cells stimulated by HSV-2-infected ECs. Addition of IL-12 and IFN-gamma at the time of initial Ag presentation enhanced CD8 cytotoxicity to levels comparable with those stimulated by the adjuvants. Addition of neutralizing Abs to IL-12 or IFN-gamma inhibited CD8 T cell cytotoxicity up to 95% when a combination of the Abs were added at the time of initial Ag presentation. Therefore, the mechanism for the enhancement of CD8 T cell cytotoxicity by adjuvants in this system appears to be via increased levels of IL-12 and IFN-gamma.
authors.affiliation: Centre for Virus Research, Westmead Millennium Institute, Westmead Hospital and University of Sydney, Westmead, Australia. zorkam@westgate.wh.usyd.edu.au
authors.forename: Z
authors.initials: Z
authors.lastname: Mikloska
authors.forename: M
authors.initials: M
authors.lastname: Rückholdt
authors.forename: I
authors.initials: I
authors.lastname: Ghadiminejad
authors.forename: H
authors.initials: H
authors.lastname: Dunckley
authors.forename: M
authors.initials: M
authors.lastname: Denis
authors.forename: A L
authors.initials: AL
authors.lastname: Cunningham
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004306:Dose-Response Relationship, Immunologic; D004338:Drug Combinations; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007106:Immune Sera / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000276:immunology; D012503:Saponins / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D044767:Ubiquitin-Protein Ligases; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D004338:Drug Combinations; C057120:ICP27 protein, human herpesvirus 1; D017874:Immediate-Early Proteins; D007106:Immune Sera; D007166:Immunosuppressive Agents; D008050:Lipid A; D011994:Recombinant Proteins; D012503:Saponins; C048925:herpes simplex virus, type 1 protein ICP4; D018664:Interleukin-12; C078785:saponin QA-21V1; D007371:Interferon-gamma; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; C048436:monophosphoryl lipid A