| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 102 === Dendritic cells (DCs) can process and present extracellular antigens on MHC class I molecules to activate cytotoxic T lymphocyte (CTL) responses through an important mechanism, antigen cross-presentation. However, toll-like receptor (TLR)-mediated cross-presentation of extracellular antigens by DCs remains unclear. In this study, models of synthetic di-palmitoylated peptides (Pam2IDG and Pam2EQL) explored the mechanisms of TLR2-mediated cross-presentation. We observed that TLR2 facilitated the internalization of di-palmitoylated peptides by bone marrow-derived DCs (BMDCs) via clathrin-mediated endocytosis. The immunization of di-palmitoylated peptide-pulsed BMDCs induced tumor regression through TLR2 signaling. These findings indicated that exogenous TLR2 agonist-conjugated peptide could be cross-presented to CTL. We further identified di-palmitoylated peptides-induced antigen-specific CTL responses was transporter associated with antigen processing (TAP) independent. In addition, endosomal acidification inhibitor (chloroquine) or a lysosomal degradation inhibitor (Z-FL-COCHO) could block the presentation of di-palmitoylated peptides by MHC class I molecules. The endocytosed di-palmitoylated peptide was delivered rapidly from early endosome antigen-1 (EEA1)-positive endosomes to RAS-related GTP-binding protein 7 (Rab7)-associated late endosomes compared with their non-lipidated counterparts. Furthermore, we found that the Rab7 expression co-related was up-regulated by di-palmitoylated peptide was via the TLR2/MyD88 pathway. Therefore, di-palmitoylated peptide could be cross-presented efficiently via vacuolar pathway to enhance CTL responses though TLR2 signaling. In conclusion, our data suggest that TLR2-mediated cross-presentation is through the upregulation of Rab7 and a vacuolar pathway to prime CTL responses.
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