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J Immunol. 2015 Feb 1;194(3):1069-79. doi: 10.4049/jimmunol.1401903. Epub 2014 Dec 17.

Induction of potent CD8 T cell cytotoxicity by specific targeting of antigen to cross-presenting dendritic cells in vivo via murine or human XCR1.

Author information

1
Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany;
2
Institute of Chemistry and Biochemistry, Free University, 14195 Berlin, Germany;
3
Department of Medicine, Rheumatology, and Clinical Immunology, Charité University Medicine, 10117 Berlin, Germany; and.
4
Biotechnology Center, Technical University, 01307 Dresden, Germany.
5
Molecular Immunology, Robert Koch-Institute, 13353 Berlin, Germany; kroczek@rki.de.

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.

PMID:
25520399
DOI:
10.4049/jimmunol.1401903
[Indexed for MEDLINE]
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