Dendritic cell maturation enhances CD8+ T-cell responses to exogenous antigen via a proteasome-independent mechanism of major histocompatibility complex class I loading.
Immune stimulating complexes (ISCOMS) containing the saponin adjuvant Quil A are vaccine adjuvants that induce a wide range of immune responses in vivo, including strong class I major histocompatibility complex (MHC)-restricted cytotoxic T-lymphocyte activity. However, the antigen-presenting cell responsible for the induction of these responses has not been characterized. Here we have investigated the role of dendritic cells (DC) in the priming of antigen-specific CD8+ T cells in vitro by ISCOMS containing ovalbumin. Resting bone marrow DC pulsed with ovalbumin ISCOMS efficiently prime resting CD8+ T cells through a mechanism that is transporter associated with antigen processing (TAP) dependent, but independent of CD40 ligation and CD4+ T-cell help. Lipopolysaccharide-induced maturation of DC markedly enhances their ability to prime CD8+ T cells through a mechanism which is also independent of CD4+ T-cell help, but is dependent on CD40 ligation. Furthermore, DC maturation revealed a TAP-independent mechanism of CD8+ T-cell priming. Our results also show that class I MHC-restricted presentation of ovalbumin in ISCOMS by DC is sensitive to chloroquine and brefeldin A but insensitive to lactacystin. We suggest that DC may be the principal antigen-presenting cells responsible for the priming of CD8+ T cells by ISCOMS in vivo and that targeting these vectors to activated DC may enhance their presentation via a novel pathway of class I antigen processing.
Robson
Neil C
NC
Department of Immunology and Bacteriology, University of Glasgow, Western Infirmary, Glasgow, UK.
Beacock-Sharp
Helen
H
Donachie
Anne M
AM
Mowat
Allan McI
AM
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D020126:Brefeldin A / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D016882:ISCOMs / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology
D019013:CD40 Antigens; D015395:Histocompatibility Antigens Class I; D016882:ISCOMs; D020126:Brefeldin A; D002738:Chloroquine; D010047:Ovalbumin