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4-1BB ligand activates bystander dendritic cells to enhance immunization in trans.
J Immunol. 2014 Nov 15; 193(10):5056-64.JI

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+Show Affiliations

Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;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.Division of Medicine, University College London, London WC1E 6BT, United Kingdom.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25305314

Citation

Macdonald, Douglas C., et al. "4-1BB Ligand Activates Bystander Dendritic Cells to Enhance Immunization in Trans." Journal of Immunology (Baltimore, Md. : 1950), vol. 193, no. 10, 2014, pp. 5056-64.
Macdonald DC, Hotblack A, Akbar S, et al. 4-1BB ligand activates bystander dendritic cells to enhance immunization in trans. J Immunol. 2014;193(10):5056-64.
Macdonald, D. C., Hotblack, A., Akbar, S., Britton, G., Collins, M. K., & Rosenberg, W. C. (2014). 4-1BB ligand activates bystander dendritic cells to enhance immunization in trans. Journal of Immunology (Baltimore, Md. : 1950), 193(10), 5056-64. https://doi.org/10.4049/jimmunol.1301723
Macdonald DC, et al. 4-1BB Ligand Activates Bystander Dendritic Cells to Enhance Immunization in Trans. J Immunol. 2014 Nov 15;193(10):5056-64. PubMed PMID: 25305314.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 4-1BB ligand activates bystander dendritic cells to enhance immunization in trans. AU - Macdonald,Douglas C, AU - Hotblack,Alastair, AU - Akbar,Saniath, AU - Britton,Gary, AU - Collins,Mary K, AU - Rosenberg,William C, Y1 - 2014/10/10/ PY - 2014/10/12/entrez PY - 2014/10/12/pubmed PY - 2015/2/25/medline SP - 5056 EP - 64 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 193 IS - 10 N2 - 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. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/25305314/4_1BB_ligand_activates_bystander_dendritic_cells_to_enhance_immunization_in_trans_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=25305314 DB - PRIME DP - Unbound Medicine ER -