title: DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8+ T cells in a spectrum of human MHC I haplotypes.
abstract: Optimal HIV vaccines should elicit CD8+ T cells specific for HIV proteins presented on MHC class I products, because these T cells contribute to host resistance to viruses. We had previously found that the targeting of antigen to dendritic cells (DCs) in mice efficiently induces CD8+ T cell responses. To extend this finding to humans, we introduced the HIV p24 gag protein into a mAb that targets DEC-205/CD205, an endocytic receptor of DCs. We then assessed cross-presentation, which is the processing of nonreplicating internalized antigen onto MHC class I for recognition by CD8+ T cells. Low doses of alphaDEC-gag, but not control Ig-gag, stimulated proliferation and IFN-gamma production by CD8+ T cells isolated from the blood of HIV-infected donors. alphaCD205 fusion mAb was more effective for cross-presentation than alphaCD209/DC-SIGN, another abundant DC uptake receptor. Presentation was diverse, because we identified eight different gag peptides that were recognized via DEC-205 in 11 individuals studied consecutively. Our results, based on humans with highly polymorphic MHC products, reveal that DCs and DEC-205 can cross-present several different peptides from a single protein. Because of the consistency in eliciting CD8+ T cell responses, these data support the testing of alphaDEC-205 fusion mAb as a protein-based vaccine.
authors.affiliation: Laboratories of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021, USA.
authors.forename: Leonia
authors.initials: L
authors.lastname: Bozzacco
authors.forename: Christine
authors.initials: C
authors.lastname: Trumpfheller
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Siegal
authors.forename: Saurabh
authors.initials: S
authors.lastname: Mehandru
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.forename: Angela Granelli
authors.initials: AG
authors.lastname: Piperno
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology*; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology*; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D015683:Gene Products, gag; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C093569:DEC-205 receptor