title: Combined NKT cell activation and influenza virus vaccination boosts memory CTL generation and protective immunity.
abstract: Current influenza A virus vaccines do not generate significant immunity against serologically distinct influenza A virus subtypes and would thus be ineffective in the face of a pandemic caused by a novel variant emerging from, say, a wildlife reservoir. One possible solution would be to modify these vaccines so that they prime cross-reactive CD8(+) cytotoxic T lymphocytes (CTL) cell-mediated immunity directed at conserved viral epitopes. A further strategy is to use novel adjuvants, such as the immunomodulatory glycolipid alpha-galactosylceramide (alpha-GalCer). We show here that giving alpha-GalCer with an inactivated influenza A virus has the paradoxical effect of diminishing acute CTL immunity via natural killer T (NKT) cell-dependent expression of indoleamine 2,3-dioxygenase (IDO), an important mediator of immune suppression, while at the same time promoting the survival of long-lived memory CTL populations capable of boosting protection against heterologous influenza A virus challenge. This enhancement of memory was likely due to the alpha-GalCer-induced upregulation of prosurvival genes, such as bcl-2, and points to the potential of alpha-GalCer as an adjuvant for promoting optimal, vaccine-induced CD8(+) T cell memory.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Melbourne 3010, Australia.
authors.forename: Carole
authors.initials: C
authors.lastname: Guillonneau
authors.forename: Justine D
authors.initials: JD
authors.lastname: Mintern
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Hubert
authors.forename: Aeron C
authors.initials: AC
authors.lastname: Hurt
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Steven
authors.initials: S
authors.lastname: Porcelli
authors.forename: Ian G
authors.initials: IG
authors.lastname: Barr
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology; D007117:Immunization, Secondary; D007156:Immunologic Memory / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D005699:Galactosylceramides; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007252:Influenza Vaccines; C493154:alpha-galactosylceramide