Journal
JOURNAL OF IMMUNOLOGY
Volume 193, Issue 10, Pages 5056-5064Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1301723
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Funding
- Medical Research Council Clinical Research Training Fellowship
- University College London Hospitals/National Institute for Health Research Biomedical Research Centre
- MRC [G0900950, G0501446, G0900374, G9721629] Funding Source: UKRI
- Medical Research Council [G0900374, G0900950, G9721629, G0501446, G0900950B, G9721629B] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10124] Funding Source: researchfish
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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.
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