Kuan-Yin Shen
National Health Research Institutes, Taiwan
Title: Molecular mechanisms of TLR2-mediated antigen cross-presentation in dendritic cells
Biography
Biography: Kuan-Yin Shen
Abstract
Cross-presentation is an important function of Dendritic Cells (DCs), which present exogenous antigens on MHC class I molecules to prime Cytotoxic T Lymphocyte (CTL) responses. The effects of Toll-Like Receptor (TLR) 2 triggering on the cross-presentation of exogenous antigens by DCs remain unclear. Here, we used synthetic di-palmitoylated peptides and TLR2 agonist-conjugated peptides as models to elucidate the mechanisms of TLR2-mediated cross-presentation. We observed that the internalization of di-palmitoylated peptides by Bone Marrow-Derived DCs ( BMDCs) was promoted by TLR2 via clathrinmediatedendocytosis. The administration of these di-palmitoylated peptide-pulsed BMDCs eliminated established tumors through TLR2 signaling. We further investigated that the induction of antigen-specific CTL responses and tumor regression by di-palmitoylated peptides was transporter associated with antigen processing (TAP) independent. Moreover, presentation of di-palmitoylated peptides by MHC class I molecules were inhibited in the presence of an endosomal acidification inhibitor (chloroquine) or a cathepsin S inhibitor (Z-FL-COCHO). The endocytosed di-palmitoylated peptide also passed 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 di-palmitoylated peptide-upregulated Rab7 expression correlated with antigen presentation via the TLR2/MyD88 pathway. Both JNK and ERK signaling pathway 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.