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The B subunit of Shiga toxin fused to a tumor antigen elicits CTL and targets dendritic cells to allow MHC class I-restricted presentation of peptides derived from exogenous antigens.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2000 Sep 15; Vol. 165 (6), pp. 3301-8. - Publication Year :
- 2000
-
Abstract
- Immunization with peptide or recombinant proteins generally fails to elicit CTL, which are thought to play a key role in the control of virus-infected cells and tumor growth. In this study we show that the nontoxic B subunit of Shiga toxin fused to a tumor peptide derived from the mouse mastocytoma P815 can induce specific CTL in mice without the use of adjuvant. The Shiga B subunit acts as a vector rather than as an adjuvant, because coinjection of the tumor peptide and the B subunit as separate entities does not lead to CTL induction. We also demonstrated that in vitro the B subunit mediates the delivery of various exogenous CD8 T cell epitopes into the conventional MHC class I-restricted pathway, as this process is inhibited by brefeldin A and lactacystin and requires a functional TAP system. In contrast to other nonviral methods for transport of exogenous Ags into the endogenous MHC class I pathway that involve macropinocytosis or phagocytosis, the Shiga B subunit targets this pathway in a receptor-dependent manner, namely via binding to the glycolipid Gb3. Because this receptor is highly expressed on various dendritic cells, it should allow preferential targeting of the Shiga B subunit to these professional APCs. Therefore, the Shiga B subunit appears to represent an attractive vector for vaccine development due to its ability to target dendritic cells and to induce specific CTL without the need for adjuvant.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 2
ATP-Binding Cassette Transporters genetics
ATP-Binding Cassette Transporters physiology
Acetylcysteine pharmacology
Animals
Antigen Presentation drug effects
Antigens, Neoplasm administration & dosage
Antigens, Neoplasm immunology
Bacterial Toxins administration & dosage
Bacterial Toxins genetics
Bacterial Toxins metabolism
Brefeldin A pharmacology
Cytotoxicity, Immunologic genetics
Dendritic Cells metabolism
Female
Injections, Intraperitoneal
Intracellular Fluid immunology
Intracellular Fluid metabolism
Leukemia L1210
Lymphocyte Activation genetics
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Knockout
Ovalbumin administration & dosage
Ovalbumin immunology
Ovalbumin metabolism
Peptides metabolism
Protein Processing, Post-Translational drug effects
Protein Processing, Post-Translational immunology
Recombinant Fusion Proteins administration & dosage
Recombinant Fusion Proteins genetics
Sarcoma, Experimental genetics
Sarcoma, Experimental immunology
Shiga Toxins
Signal Transduction genetics
Signal Transduction immunology
T-Lymphocytes, Cytotoxic metabolism
Tumor Cells, Cultured
Acetylcysteine analogs & derivatives
Antigen Presentation genetics
Antigens, Neoplasm genetics
Bacterial Toxins immunology
Dendritic Cells immunology
Histocompatibility Antigens Class I immunology
Peptides immunology
Recombinant Fusion Proteins immunology
T-Lymphocytes, Cytotoxic immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1767
- Volume :
- 165
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 10975847
- Full Text :
- https://doi.org/10.4049/jimmunol.165.6.3301