title: 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.
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.
authors.affiliation: Unité d'Immunologie Clinique, Institut de la Santé et de la Recherche Médicale, Unité 255, Université Pierre et Marie Curie, Institut Curie, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Haicheur
authors.forename: E
authors.initials: E
authors.lastname: Bismuth
authors.forename: S
authors.initials: S
authors.lastname: Bosset
authors.forename: O
authors.initials: O
authors.lastname: Adotevi
authors.forename: G
authors.initials: G
authors.lastname: Warnier
authors.forename: V
authors.initials: V
authors.lastname: Lacabanne
authors.forename: A
authors.initials: A
authors.lastname: Regnault
authors.forename: C
authors.initials: C
authors.lastname: Desaymard
authors.forename: S
authors.initials: S
authors.lastname: Amigorena
authors.forename: P
authors.initials: P
authors.lastname: Ricciardi-Castagnoli
authors.forename: B
authors.initials: B
authors.lastname: Goud
authors.forename: W H
authors.initials: WH
authors.lastname: Fridman
authors.forename: L
authors.initials: L
authors.lastname: Johannes
authors.forename: E
authors.initials: E
authors.lastname: Tartour
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020126:Brefeldin A / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007274:Injections, Intraperitoneal; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D007939:Leukemia L1210; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D012513:Sarcoma, Experimental / Q000235:genetics / Q000276:immunology; D022603:Shiga Toxins; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000951:Antigens, Neoplasm; D001427:Bacterial Toxins; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D011993:Recombinant Fusion Proteins; D022603:Shiga Toxins; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; C067713:lactacystin; D020126:Brefeldin A; D010047:Ovalbumin; D000111:Acetylcysteine