The Shiga toxin B-subunit targets antigen in vivo to dendritic cells and elicits anti-tumor immunity.
The non-toxic B-subunit of Shiga toxin (STxB) interacts with the glycolipid Gb3, which is preferentially expressed on dendritic cells (DC) and B cells. After administration of STxB chemically coupled to OVA (STxB-OVA) in mice, we showed that the immunodominant OVA(257-264) peptide restricted by K(b) molecules is specifically presented by CD11c+ CD8alpha- DC, some of them displaying a mature phenotype. Using mice carrying a transgene encoding a diphtheria toxin receptor (DTR) under the control of the murine CD11c promoter, which allows inducible ablation of DC, we showed that DC are required for efficient priming of CTL after STxB-OVA vaccination. Immunization of mice with STxB-OVA induced OVA-specific CD8+ T cells detected ex vivo; these cells were long lasting, since they could be detected even 91 days after the last immunization and were composed of both central and memory T cells. Vaccination of mice with STxB-OVA and STxB coupled to E7, a protein derived from HPV16, inhibited tumor growth in prophylactic and therapeutic experiments. This effect was mainly mediated by CD8+ T cells. STxB therefore appears to be a powerful carrier directly targeting DC in vivo, resulting in a strong and durable CTL response associated with tumor protection.
INSERM U255, Université René Descartes, Unité d'Immunologie Biologique, Hopital Européen Georges Pompidou AP-HP, Paris, France.
Benoit
B
Vingert
Olivier
O
Adotevi
Delphine
D
Patin
Steffen
S
Jung
Protul
P
Shrikant
Ludovic
L
Freyburger
Cheryl
C
Eppolito
Anita
A
Sapoznikov
Mohamed
M
Amessou
Françoise
F
Quintin-Colonna
Wolf Herman
WH
Fridman
Ludger
L
Johannes
Eric
E
Tartour
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D016219:Immunotherapy, Adoptive; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D010047:Ovalbumin / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D022603:Shiga Toxins / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014611:Vaccination
D010446:Peptide Fragments; D022603:Shiga Toxins; C077239:stxB toxin; D010047:Ovalbumin