Enhanced endoplasmic reticulum entry of tumor antigen is crucial for cross-presentation induced by dendritic cell-targeted vaccination.

Abstract

Efficient cross-presentation of protein Ags to CTLs by dendritic cells (DCs) is essential for the success of prophylactic and therapeutic vaccines. In this study, we report a previously underappreciated pathway involving Ag entry into the endoplasmic reticulum (ER) critically needed for T cell cross-priming induced by a DC-targeted vaccine. Directing the clinically relevant, melanoma Ag gp100 to mouse-derived DCs by molecular adjuvant and chaperone Grp170 substantially facilitates Ag access to the ER. Grp170 also strengthens the interaction of internalized protein Ag with molecular components involved in ER-associated protein dislocation and/or degradation, which culminates in cytosolic translocation for proteasome-dependent degradation and processing. Targeted disruption of protein retrotranslocation causes exclusive ER retention of tumor Ag in mouse bone marrow-derived DCs and splenic CD8(+) DCs. This results in the blockade of Ag ubiquitination and processing, which abrogates the priming of Ag-specific CD8(+) T cells in vitro and in vivo. Therefore, the improved ER entry of tumor Ag serves as a molecular basis for the superior cross-presenting capacity of Grp170-based vaccine platform. The ER access and retrotranslocation represents a distinct pathway that operates within DCs for cross-presentation and is required for the activation of Ag-specific CTLs by certain vaccines. These results also reinforce the importance of the ER-associated protein quality control machinery and the mode of the Ag delivery in regulating DC-elicited immune outcomes.

• Authors: Hongxia Wang, Xiaofei Yu, Chunqing Guo, Daming Zuo, Paul B Fisher, John R Subjeck, Xiang-Yang Wang
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 191 Issue 12 Pg. 6010-21 (Dec 15 2013) ISSN: 1550-6606 [Electronic] United States
• PMID: 24218449 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Bacterial Toxins
• Cancer Vaccines
• Exotoxins
• Glycoproteins
• HSP70 Heat-Shock Proteins
• Membrane Proteins
• RNA, Small Interfering
• Recombinant Fusion Proteins
• SEC Translocation Channels
• SEC61A1 protein, mouse
• Virulence Factors
• glucose-regulated protein 170
• gp100 Melanoma Antigen
• ADP Ribose Transferases
• Pseudomonas aeruginosa exotoxin A

Topics

• ADP Ribose Transferases (pharmacology)
• Adjuvants, Immunologic
• Adoptive Transfer
• Animals
• Antigen Presentation (immunology)
• Bacterial Toxins (pharmacology)
• Bone Marrow Cells (immunology)
• Cancer Vaccines (immunology, pharmacokinetics)
• Cell Lineage
• Cells, Cultured
• Cross-Priming (immunology)
• Cytosol (metabolism)
• Dendritic Cells (classification, immunology)
• Endocytosis (immunology)
• Endoplasmic Reticulum (immunology)
• Endosomes (metabolism)
• Exotoxins (pharmacology)
• Glycoproteins (immunology)
• HSP70 Heat-Shock Proteins (immunology)
• Membrane Proteins (antagonists & inhibitors, genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Protein Processing, Post-Translational
• Protein Transport
• Proteolysis
• RNA, Small Interfering (pharmacology)
• Recombinant Fusion Proteins (immunology, pharmacokinetics)
• SEC Translocation Channels
• Spleen (cytology, immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Ubiquitination
• Vaccination (methods)
• Virulence Factors (pharmacology)
• gp100 Melanoma Antigen (genetics, immunology, pharmacokinetics)