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

Kim, Jocelyn T. and Liu, Yarong and Kulkarni, Rajan P. and Lee, Kevin K. and Dai, Bingbing and Lovely, Geoffrey and Ouyang, Yong and Wang, Pin and Yang, Lili and Baltimore, David (2017) Dendritic cell–targeted lentiviral vector immunization uses pseudotransduction and DNA-mediated STING and cGAS activation. Science Immunology, 2 (13). Art. No. eaal1329. ISSN 2470-9468. PMCID PMC5845465. http://resolver.caltech.edu/CaltechAUTHORS:20170718-091900989

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Abstract

Dendritic cell (DC) activation and antigen presentation are critical for efficient priming of T cell responses. Here, we study how lentiviral vectors (LVs) deliver antigen and activate DCs to generate T cell immunization in vivo. We report that antigenic proteins delivered in vector particles via pseudotransduction were sufficient to stimulate an antigen-specific immune response. The delivery of the viral genome encoding the antigen increased the magnitude of this response in vivo but was irrelevant in vitro. Activation of DCs by LVs was independent of MyD88, TRIF, and MAVS, ruling out an involvement of Toll-like receptor or RIG-I–like receptor signaling. Cellular DNA packaged in LV preparations induced DC activation by the host STING (stimulator of interferon genes) and cGAS (cyclic guanosine monophosphate–adenosine monophosphate synthase) pathway. Envelope-mediated viral fusion also activated DCs in a phosphoinositide 3-kinase–dependent but STING-independent process. Pseudotransduction, transduction, viral fusion, and delivery of cellular DNA collaborate to make the DC-targeted LV preparation an effective immunogen.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1126/sciimmunol.aal1329DOIArticle
http://immunology.sciencemag.org/content/2/13/eaal1329PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845465PubMed CentralArticle
ORCID:
AuthorORCID
Kim, Jocelyn T.0000-0001-8723-8190
Baltimore, David0000-0001-8723-8190
Additional Information:© 2017 American Association for the Advancement of Science. We thank G. Cheng (UCLA) for the MAVS−/− mice, Z. Chen (University of Texas Southwestern Medical Center) for the cGAS−/− mice, the UCLA/CFAR Virology Core Laboratory (5P30 AI028697), the UCLA Specialty Training and Advanced Research Program, the AIDS Reagent Program, the National Institute of Allergy and Infectious Diseases Tetramer Core Facility, the UCLA/CFAR Virology Core Laboratory, and the PrimerBank. This work was supported by the Millard and Muriel Jacobs Genetics and Genomics Laboratory at Caltech. We thank M. Bethune and G. Li for the review of the manuscript. Data and materials availability: DNA sequence data have been deposited in Sequence Read Archive under accession number SAMN07195639. Funding: This work was supported by the NIH (OPPGH5157) and the American Foundation for AIDS Research (108292-51-RGRL). J.T.K. was supported by the NIH (KL2TR001882) and the UCLA Specialty Training and Advanced Research (STAR) Program. Author contributions: J.T.K. designed the research, performed the experiments, analyzed the results, and drafted the manuscript. Y.L., B.D., G.L., R.P.K., K.K.L., and Y.O. performed the experiments. L.Y. and P.W. discussed the results and drafted the manuscript. D.B. designed the research, discussed the results, drafted the manuscript, and provided financial support.
Funders:
Funding AgencyGrant Number
NIHOPPGH5157
American Foundation for AIDS Research108292-51-RGRL
NIHKL2TR001882
UCLA Specialty Training and Advanced Research (STAR) ProgramUNSPECIFIED
PubMed Central ID:PMC5845465
Record Number:CaltechAUTHORS:20170718-091900989
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20170718-091900989
Official Citation:Dendritic cell–targeted lentiviral vector immunization uses pseudotransduction and DNA-mediated STING and cGAS activation BY JOCELYN T. KIM, YARONG LIU, RAJAN P. KULKARNI, KEVIN K. LEE, BINGBING DAI, GEOFFREY LOVELY, YONG OUYANG, PIN WANG, LILI YANG, DAVID BALTIMORE SCIENCE IMMUNOLOGY21 JUL 2017
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:79147
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:21 Jul 2017 19:52
Last Modified:12 Mar 2018 16:24

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