B subunit of Shiga toxin-based vaccines synergize with alpha-galactosylceramide to break tolerance against self antigen and elicit antiviral immunity.
The nontoxic B subunit of Shiga toxin (STxB) targets in vivo Ag to dendritic cells that preferentially express the glycolipid Gb(3) receptor. After administration of STxB chemically coupled to OVA (STxB-OVA) or E7, a polypeptide derived from HPV, in mice, we showed that the addition of alpha-galactosylceramide (alpha-GalCer) resulted in a dramatic improvement of the STxB Ag delivery system, as reflected by the more powerful and longer lasting CD8(+) T cell response observed even at very low dose of immunogen (50 ng). This synergy was not found with other adjuvants (CpG, poly(I:C), IFN-alpha) also known to promote dendritic cell maturation. With respect to the possible mechanism explaining this synergy, mice immunized with alpha-GalCer presented in vivo the OVA(257-264)/K(b) complex more significantly and for longer period than mice vaccinated with STxB alone or mixed with other adjuvants. To test whether this vaccine could break tolerance against self Ag, OVA transgenic mice were immunized with STxB-OVA alone or mixed with alpha-GalCer. Although no CTL induction was observed after immunization of OVA transgenic mice with STxB-OVA, tetramer assay clearly detected specific anti-OVA CD8(+) T cells in 8 of 11 mice immunized with STxB-OVA combined with alpha-GalCer. In addition, vaccination with STxB-OVA and alpha-GalCer conferred strong protection against a challenge with vaccinia virus encoding OVA with virus titers in the ovaries reduced by 5 log compared with nonimmunized mice. STxB combined with alpha-GalCer therefore appears as a promising vaccine strategy to more successfully establish protective CD8(+) T cell memory against intracellular pathogens and tumors.
Adotevi
Olivier
O
Equipe d'accueil 4054 Université Paris-Descartes, Ecole Nationale Vétérinaire d'Alfort, Paris, France.
Vingert
Benoit
B
Freyburger
Ludovic
L
Shrikant
Protul
P
Lone
Yu-Chun
YC
Quintin-Colonna
Françoise
F
Haicheur
Nacilla
N
Amessou
Mohamed
M
Herbelin
André
A
Langlade-Demoyen
Pierre
P
Fridman
Wolf H
WH
Lemonnier
François
F
Johannes
Ludger
L
Tartour
Eric
E
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004357:Drug Synergism; D005699:Galactosylceramides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000276:immunology; D010047:Ovalbumin / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D022603:Shiga Toxins / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D014614:Vaccines, Synthetic / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D014615:Vaccinia / Q000517:prevention & control*; D014616:Vaccinia virus / Q000276:immunology
D001324:Autoantigens; D005699:Galactosylceramides; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010455:Peptides; D022603:Shiga Toxins; D014614:Vaccines, Synthetic; C493154:alpha-galactosylceramide; C059731:oncogene protein E7, Human papillomavirus type 16; C077239:stxB toxin; D010047:Ovalbumin