title: Costimulatory molecule immune enhancement in a plasmid vaccine model is regulated in part through the Ig constant-like domain of CD80/86.
abstract: There is great interest in understanding the role of costimulatory molecules in immune activation. In both the influenza and HIV DNA immunization models, several groups have reported that coimmunization of mice with plasmids encoding immunogen and CD86, but not CD80, effectively boosts Ag-specific T cell activation. This difference in immune priming provided an opportunity to examine the functional importance of different regions of the B.7 molecules in immune activation. To examine this issue, we developed a series of chimeric CD80 and CD86 constructs as well as deletion mutants, and examined their immune activating potential in the DNA vaccine model. We demonstrate that the lack of an Ig constant-like region in the CD80 molecule is critically important to the enhanced immune activation observed. CD80 C-domain deletion mutants induce a highly inflammatory Ag-specific cellular response when administered as part of a plasmid vaccine. The data suggest that the constant-like domains, likely through intermolecular interactions, are critically important for immune regulation during costimulation and that engineered CD80/86 molecules represent more potent costimulatory molecules and may improve vaccine adjuvant efficacy.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Agadjanyan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Chattergoon
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Holterman
authors.forename: Behjatolah
authors.initials: B
authors.lastname: Monzavi-Karbassi
authors.forename: J Joseph
authors.initials: JJ
authors.lastname: Kim
authors.forename: Tzvete
authors.initials: T
authors.lastname: Dentchev
authors.forename: Darren
authors.initials: D
authors.lastname: Wilson
authors.forename: Velpandi
authors.initials: V
authors.lastname: Ayyavoo
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
authors.forename: Thomas
authors.initials: T
authors.lastname: Kieber-Emmons
authors.forename: Rafick-P
authors.initials: RP
authors.lastname: Sekaly
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018122:B7-1 Antigen / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051940:B7-2 Antigen; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D007135:Immunoglobulin Variable Region / Q000008:administration & dosage / Q000235:genetics; D016131:Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018448:Models, Immunological; D016297:Mutagenesis, Site-Directed; D010957:Plasmids; D017434:Protein Structure, Tertiary / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D017384:Sequence Deletion / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013539:Simian virus 40 / Q000235:genetics / Q000276:immunology; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D007127:Immunoglobulin Constant Regions; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA