title: Molecular mechanisms of TLR2-mediated antigen cross-presentation in dendritic cells.
abstract: Cross-presentation is a key function of dendritic cells (DCs), which present exogenous Ags on MHC class I molecules to prime CTL responses. The effects of TLR triggering on the cross-presentation of exogenous Ags by DCs remain unclear. In this study, we used synthetic dipalmitoylated peptides and TLR2 agonist-conjugated peptides as models to elucidate the mechanisms of TLR2-mediated cross-presentation. We observed that the internalization of dipalmitoylated peptides by bone marrow-derived DCs was facilitated by TLR2 via clathrin-mediated endocytosis. The administration of these dipalmitoylated peptide-pulsed bone marrow-derived DCs eliminated established tumors through TLR2 signaling. We further demonstrated that the induction of Ag-specific CTL responses and tumor regression by dipalmitoylated peptides was TAP independent. In addition, presentation of dipalmitoylated peptides by MHC class I molecules was blocked in the presence of an endosomal acidification inhibitor (chloroquine) or a lysosomal degradation inhibitor (Z-FL-COCHO). The endocytosed dipalmitoylated peptide also passed rapidly from early endosome Ag-1-positive endosomes to RAS-related GTP-binding protein 7 (Rab7)-associated late endosomes compared with their nonlipidated counterparts. Furthermore, we found that dipalmitoylated peptide-upregulated Rab7 expression correlated with Ag presentation via the TLR2/MyD88 pathway. Both JNK and ERK signaling pathways are required for upregulation of Rab7. In summary, our data suggest that TLR2-mediated cross-presentation occurs through the upregulation of Rab7 and a TAP-independent pathway that prime CTL responses.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan;
authors.forename: Kuan-Yin
authors.initials: KY
authors.lastname: Shen
authors.forename: Ying-Chyi
authors.initials: YC
authors.lastname: Song
authors.forename: I-Hua
authors.initials: IH
authors.lastname: Chen
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Leng
authors.forename: Hsin-Wei
authors.initials: HW
authors.lastname: Chen
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Li
authors.forename: Pele
authors.initials: P
authors.lastname: Chong
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045142:Cross-Priming / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009374:Neoplasms, Experimental / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D020691:rab GTP-Binding Proteins / Q000276:immunology; D000090802:rab7 GTP-Binding Proteins
chemical_list: C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D000090802:rab7 GTP-Binding Proteins; C000716465:rab7 GTP-binding proteins, mouse; D020691:rab GTP-Binding Proteins