Dendritic cell maturation enhances CD8+ T-cell responses to exogenous antigen via a proteasome-independent mechanism of major histocompatibility complex class I loading

摘要

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.