title: Priming of CD8 T cells by adenoviral vectors is critically dependent on B7 and dendritic cells but only partially dependent on CD28 ligation on CD8 T cells.
abstract: Adenoviral vectors have long been forerunners in the development of effective CD8 T cell-based vaccines; therefore, it is imperative that we understand the factors controlling the induction of robust and long-lasting transgene-specific immune responses by these vectors. In this study, we investigated the organ sites, molecules, and cell subsets that play a critical role in the priming of transgene-specific CD8 T cells after vaccination with a replication-deficient adenoviral vector. Using a human adenovirus serotype 5 (Ad5) vector and genetically engineered mice, we found that CD8(+) and/or CD103(+) dendritic cells in the draining lymph node played a critical role in the priming of Ad5-induced CD8 T cell responses. Moreover, we found that CD80/86, but not CD28, was essential for efficient generation of both primary effectors and memory CD8 T cells. Interestingly, the lack of CD28 expression resulted in a delayed primary response, whereas memory CD8 T cells generated in CD28-deficient mice appeared almost normal in terms of both phenotype and effector cytokine profile, but they exhibited a significantly reduced proliferative capacity upon secondary challenge while retaining immediate in vivo effector capabilities: in vivo cytotoxicity and short-term in vivo protective capacity. Overall, our data point to an absolute requirement for professional APCs and the expression of the costimulatory molecules CD80/86 for efficient CD8 T cell priming by adenoviral vectors. Additionally, our results suggest the existence of an alternative receptor for CD80/86, which may substitute, in part, for CD28.
authors.affiliation: Department of International Health, Immunology, and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Karen N
authors.initials: KN
authors.lastname: Nielsen
authors.affiliation: Department of International Health, Immunology, and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Steffensen
authors.affiliation: Department of International Health, Immunology, and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Christensen
authors.affiliation: Department of International Health, Immunology, and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark athomsen@sund.ku.dk.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Thomsen
mesh_terms: D000258:Adenovirus Infections, Human / Q000235:genetics / Q000517:prevention & control*; D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018122:B7-1 Antigen / Q000172:deficiency* / Q000235:genetics; D051940:B7-2 Antigen / Q000172:deficiency* / Q000235:genetics; D018106:CD28 Antigens / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005260:Female; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D008024:Ligands; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014611:Vaccination
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D008024:Ligands