Jensen, Søren5; Steffensen, Maria Abildgaard6; Jensen, Benjamin Anderschou Holbech7; Schlüter, Dirk4; Christensen, Jan Pravsgaard5; Thomsen, Allan Randrup5
1 Department of Immunology and Microbiology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet2 Genome Research and Molecular Bio Medicine, Department of Biology, Faculty of Science, Københavns Universitet3 Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet4 Otto-von-Guericke Universität, Magdeburg5 Department of Immunology and Microbiology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet6 Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet7 Genome Research and Molecular Bio Medicine, Department of Biology, Faculty of Science, Københavns Universitet
extending the concept of invariant chain linkage
The use of replication-deficient adenoviruses as vehicles for transfer of foreign genes offers many advantages in a vaccine setting, eliciting strong cellular immune responses involving both CD8(+) and CD4(+) T cells. Further improving the immunogenicity, tethering of the inserted target Ag to MHC class II-associated invariant chain (Ii) greatly enhances both the presentation of most target Ags, as well as overall protection against viral infection, such as lymphocytic choriomeningitis virus (LCMV). The present study extends this vaccination concept to include protection against intracellular bacteria, using Listeria monocytogenes as a model organism. Protection in C57BL/6 mice against recombinant L. monocytogenes expressing an immunodominant epitope of the LCMV glycoprotein (GP33) was greatly accelerated, augmented, and prolonged following vaccination with an adenoviral vaccine encoding GP linked to Ii compared with vaccination with the unlinked vaccine. Studies using knockout mice demonstrated that CD8(+) T cells were largely responsible for this protection, which is mediated through perforin-dependent lysis of infected cells and IFN-γ production. Taking the concept a step further, vaccination of C57BL/6 (L. monocytogenes-resistant) and BALB/c (L. monocytogenes-susceptible) mice with adenoviral vectors encoding natural L. monocytogenes-derived soluble Ags (listeriolysin O and p60) revealed that tethering of these Ags to Ii markedly improved the vaccine-induced CD8(+) T cell response to two of three epitopes studied. More importantly, Ii linkage accelerated and augmented vaccine-induced protection in both mouse strains and prolonged protection, in particular that induced by the weak Ag, p60, in L. monocytogenes-susceptible BALB/c mice.
Journal of Immunology (baltimore, Md. : 1950), 2013, Vol 191, Issue 8, p. 4152-4164