title: 4-1BB ligand activates bystander dendritic cells to enhance immunization in trans.
abstract: Expression of the costimulatory receptor 4-1BB is induced by TCR recognition of Ag, whereas 4-1BB ligand (4-1BBL) is highly expressed on activated APC. 4-1BB signaling is particularly important for survival of activated and memory CD8(+) T cells. We wished to test whether coexpression of Ag and 4-1BBL by dendritic cells (DC) would be an effective vaccine strategy. Therefore, we constructed lentiviral vectors (LV) coexpressing 4-1BBL and influenza nucleoprotein (NP). Following s.c. immunization of mice, which targets DC, we found superior CD8(+) T cell responses against NP and protection from influenza when 4-1BBL was expressed. However, functionally superior CD8(+) T cell responses were obtained when two LV were coinjected: one expressing 4-1BBL and the other expressing NP. This surprising result suggested that 4-1BBL is more effective when expressed in trans, acting on adjacent DC. Therefore, we investigated the effect of LV expression of 4-1BBL in mouse DC cultures and observed induced maturation of bystander, untransduced cells. Maturation was blocked by anti-4-1BBL Ab, required cell-cell contact, and did not require the cytoplasmic signaling domain of 4-1BBL. Greater maturation of untransduced cells could be explained by LV expression of 4-1BBL, causing downregulation of 4-1BB. These data suggest that coexpression of 4-1BBL and Ag by vaccine vectors that target DC may not be an optimal strategy. However, 4-1BBL LV immunization activates significant numbers of bystander DC in the draining lymph nodes. Therefore, transactivation by 4-1BBL/4-1BB interaction following DC-DC contact may play a role in the immune response to infection or vaccination.
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Macdonald
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Alastair
authors.initials: A
authors.lastname: Hotblack
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Saniath
authors.initials: S
authors.lastname: Akbar
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Gary
authors.initials: G
authors.lastname: Britton
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom; National Institute for Biological Standards and Control, South Mimms, Potters Bar, Hertsfordshire EN6 3QG, United Kingdom; and mary.collins@ucl.ac.uk.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Collins
authors.affiliation: Division of Medicine, University College London, London WC1E 6BT, United Kingdom.
authors.forename: William C
authors.initials: WC
authors.lastname: Rosenberg
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D024201:Bystander Effect; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D007114:Immunization; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009975:Orthomyxoviridae / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control*; D015398:Signal Transduction; D015533:Transcriptional Activation; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D000956:Antigens, Viral; D007252:Influenza Vaccines; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014758:Viral Core Proteins