title: Induction of potent CD8 T cell cytotoxicity by specific targeting of antigen to cross-presenting dendritic cells in vivo via murine or human XCR1.
abstract: Current subunit vaccines are incapable of inducing Ag-specific CD8(+) T cell cytotoxicity needed for the defense of certain infections and for therapy of neoplastic diseases. In experimental vaccines, cytotoxic responses can be elicited by targeting of Ag into cross-presenting dendritic cells (DC), but almost all available systems use target molecules also expressed on other cells and thus lack the desired specificity. In the present work, we induced CD8(+) T cell cytotoxicity by targeting of Ag to XCR1, a chemokine receptor exclusively expressed on murine and human cross-presenting DC. Targeting of Ag with a mAb or the chemokine ligand XCL1 was highly specific, as determined with XCR1-deficient mice. When applied together with an adjuvant, both vector systems induced a potent cytotoxic response preventing the outgrowth of an inoculated aggressive tumor. By generating a transgenic mouse only expressing the human XCR1 on its cross-presenting DC, we could demonstrate that targeting of Ag using human XCL1 as vector is fully effective in vivo. The specificity and efficiency of XCR1-mediated Ag targeting to cross-presenting DC, combined with its lack of adverse effects, make this system a prime candidate for the development of therapeutic cytotoxic vaccines in humans.
authors.affiliation: Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany;
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hartung
authors.affiliation: Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany;
authors.forename: Martina
authors.initials: M
authors.lastname: Becker
authors.affiliation: Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany;
authors.forename: Annabell
authors.initials: A
authors.lastname: Bachem
authors.affiliation: Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany;
authors.forename: Nele
authors.initials: N
authors.lastname: Reeg
authors.affiliation: Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany;
authors.forename: Anika
authors.initials: A
authors.lastname: Jäkel
authors.affiliation: Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Hutloff
authors.affiliation: Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany;
authors.forename: Harald
authors.initials: H
authors.lastname: Weber
authors.affiliation: Institute of Chemistry and Biochemistry, Free University, 14195 Berlin, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Weise
authors.affiliation: Department of Medicine, Rheumatology, and Clinical Immunology, Charité University Medicine, 10117 Berlin, Germany; and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Giesecke
authors.affiliation: Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany;
authors.forename: Volker
authors.initials: V
authors.lastname: Henn
authors.affiliation: Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gurka
authors.affiliation: Biotechnology Center, Technical University, 01307 Dresden, Germany.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Anastassiadis
authors.affiliation: Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany;
authors.forename: Hans W
authors.initials: HW
authors.lastname: Mages
authors.affiliation: Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany; kroczek@rki.de.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kroczek
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D000941:Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D019496:Cancer Vaccines / Q000276:immunology; D002454:Cell Differentiation; D045142:Cross-Priming / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D017578:Immunoglobulin Class Switching; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D019496:Cancer Vaccines; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; C551408:XC chemokine receptor 1, mouse; C091671:XCR1 protein, human