Lentiviral Vectors Transduce Proliferating Dendritic Cell Precursors Leading to Persistent Antigen Presentation and Immunization

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2009 Jul 9

PMID 19584812

Citations 18

Authors

Frederick Arce

Helen M Rowe

Benjamin Chain

Luciene Lopes

Mary K Collins

Affiliations

Soon will be listed here.

Abstract

Lentiviral vectors (LVs) are tools for in vivo gene delivery, to correct genetic defects or to deliver antigens for vaccination. It was reported that systemic injection of LVs in mice transduced cells in liver and spleen. Here we describe the reasons for, and consequences of, persistent gene expression in spleen. After 5 days of intravenous injection, a green fluorescence protein (GFP)-expressing LV was detected in lymphocytes, macrophages and all subsets of dendritic cells (DCs) in spleen. In the case of macrophages and DCs, the percentage of transduced cells increased between 5 and 30 days after injection. We used bromodeoxyuridine (BrdU) incorporation to show that the macrophages were largely nondividing, whereas the transduced DCs arose from dividing precursor cells and could be detected in spleen 2 months after injection. Expression of ovalbumin (OVA) in the LV reduced the number of transduced DCs in spleen after 30 days. However, the remaining transduced cells stimulated proliferation and activation of OVA-specific CD8(+) T cells transferred 2 months after LV injection. The mice also maintained cytolytic activity against OVA-pulsed targets. These results show that LVs transduce DC precursors, which maintain transduced DCs in spleen for at least 2 months, leading to prolonged antigen presentation and effective T-cell memory.

Citing Articles

Editing T cell repertoire by thymic epithelial cell-directed gene transfer abrogates risk of type 1 diabetes development.

Russo F, Ruggiero E, Curto R, Passeri L, Sanvito F, Bortolomai I Mol Ther Methods Clin Dev. 2022; 25:508-519.

PMID: 35615710 PMC: 9121074. DOI: 10.1016/j.omtm.2022.04.017.

Brain cross-protection against SARS-CoV-2 variants by a lentiviral vaccine in new transgenic mice.

Ku M, Authie P, Bourgine M, Anna F, Noirat A, Moncoq F EMBO Mol Med. 2021; 13(12):e14459.

PMID: 34647691 PMC: 8646827. DOI: 10.15252/emmm.202114459.

Dendritic cell-targeted lentiviral vector immunization uses pseudotransduction and DNA-mediated STING and cGAS activation.

Kim J, Liu Y, Kulkarni R, Lee K, Dai B, Lovely G Sci Immunol. 2017; 2(13).

PMID: 28733470 PMC: 5845465. DOI: 10.1126/sciimmunol.aal1329.

Dendritic Cells Cross-Present Immunogenic Lentivector-Encoded Antigen from Transduced Cells to Prime Functional T Cell Immunity.

Hotblack A, Seshadri S, Zhang L, Hamrang-Yousefi S, Chakraverty R, Escors D Mol Ther. 2017; 25(2):504-511.

PMID: 28153097 PMC: 5368353. DOI: 10.1016/j.ymthe.2016.11.001.

Tissue-resident dendritic cells and diseases involving dendritic cell malfunction.

Chen K, Wang J, Yuan R, Yi X, Li L, Gong W Int Immunopharmacol. 2016; 34:1-15.

PMID: 26906720 PMC: 4818737. DOI: 10.1016/j.intimp.2016.02.007.

References

Karwacz K, Mukherjee S, Apolonia L, Blundell M, Bouma G, Escors D . Nonintegrating lentivector vaccines stimulate prolonged T-cell and antibody responses and are effective in tumor therapy. J Virol. 2009; 83(7):3094-103. PMC: 2655594. DOI: 10.1128/JVI.02519-08. View

Nguyen T, Aubert D, Bellodi-Privato M, Flageul M, Pichard V, Jaidane-Abdelghani Z . Critical assessment of lifelong phenotype correction in hyperbilirubinemic Gunn rats after retroviral mediated gene transfer. Gene Ther. 2007; 14(17):1270-7. DOI: 10.1038/sj.gt.3302993. View

Naik S, Metcalf D, Van Nieuwenhuijze A, Wicks I, Wu L, OKeeffe M . Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat Immunol. 2006; 7(6):663-71. DOI: 10.1038/ni1340. View

Redmond W, Sherman L . Peripheral tolerance of CD8 T lymphocytes. Immunity. 2005; 22(3):275-84. DOI: 10.1016/j.immuni.2005.01.010. View

Bevan M, Fink P . The CD8 response on autopilot. Nat Immunol. 2001; 2(5):381-2. DOI: 10.1038/87676. View

Simon I, Publicover J, Rose J . Replication and propagation of attenuated vesicular stomatitis virus vectors in vivo: vector spread correlates with induction of immune responses and persistence of genomic RNA. J Virol. 2006; 81(4):2078-82. PMC: 1797556. DOI: 10.1128/JVI.02525-06. View

Shortman K, Liu Y . Mouse and human dendritic cell subtypes. Nat Rev Immunol. 2002; 2(3):151-61. DOI: 10.1038/nri746. View

Peng K, Pham L, Ye H, Zufferey R, Trono D, Cosset F . Organ distribution of gene expression after intravenous infusion of targeted and untargeted lentiviral vectors. Gene Ther. 2001; 8(19):1456-63. DOI: 10.1038/sj.gt.3301552. View

Merle U, Encke J, Tuma S, Volkmann M, Naldini L, Stremmel W . Lentiviral gene transfer ameliorates disease progression in Long-Evans cinnamon rats: an animal model for Wilson disease. Scand J Gastroenterol. 2006; 41(8):974-82. DOI: 10.1080/00365520600554790. View

10.

He Y, Zhang J, Donahue C, Falo Jr L . Skin-derived dendritic cells induce potent CD8(+) T cell immunity in recombinant lentivector-mediated genetic immunization. Immunity. 2006; 24(5):643-56. PMC: 3077717. DOI: 10.1016/j.immuni.2006.03.014. View

11.

Escors D, Lopes L, Lin R, Hiscott J, Akira S, Davis R . Targeting dendritic cell signaling to regulate the response to immunization. Blood. 2008; 111(6):3050-61. DOI: 10.1182/blood-2007-11-122408. View

12.

Hernandez J, Aung S, Redmond W, Sherman L . Phenotypic and functional analysis of CD8(+) T cells undergoing peripheral deletion in response to cross-presentation of self-antigen. J Exp Med. 2001; 194(6):707-17. PMC: 2195957. DOI: 10.1084/jem.194.6.707. View

13.

Rowe H, Lopes L, Ikeda Y, Bailey R, Barde I, Zenke M . Immunization with a lentiviral vector stimulates both CD4 and CD8 T cell responses to an ovalbumin transgene. Mol Ther. 2005; 13(2):310-9. DOI: 10.1016/j.ymthe.2005.08.025. View

14.

Kimura T, Koya R, Anselmi L, Sternini C, Wang H, Comin-Anduix B . Lentiviral vectors with CMV or MHCII promoters administered in vivo: immune reactivity versus persistence of expression. Mol Ther. 2007; 15(7):1390-9. DOI: 10.1038/sj.mt.6300180. View

15.

Obst R, van Santen H, Mathis D, Benoist C . Antigen persistence is required throughout the expansion phase of a CD4(+) T cell response. J Exp Med. 2005; 201(10):1555-65. PMC: 2212918. DOI: 10.1084/jem.20042521. View

16.

Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig M, Steinman R . Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med. 2002; 196(12):1627-38. PMC: 2196060. DOI: 10.1084/jem.20021598. View

17.

Breckpot K, Emeagi P, Dullaers M, Michiels A, Heirman C, Thielemans K . Activation of immature monocyte-derived dendritic cells after transduction with high doses of lentiviral vectors. Hum Gene Ther. 2007; 18(6):536-46. DOI: 10.1089/hum.2007.006. View

18.

Ahmed R, Gray D . Immunological memory and protective immunity: understanding their relation. Science. 1996; 272(5258):54-60. DOI: 10.1126/science.272.5258.54. View

19.

Lopes L, Dewannieux M, Gileadi U, Bailey R, Ikeda Y, Whittaker C . Immunization with a lentivector that targets tumor antigen expression to dendritic cells induces potent CD8+ and CD4+ T-cell responses. J Virol. 2007; 82(1):86-95. PMC: 2224357. DOI: 10.1128/JVI.01289-07. View

20.

Kamath A, Henri S, Battye F, Tough D, Shortman K . Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. Blood. 2002; 100(5):1734-41. View