Enhanced virus-specific CD8+ T cell responses by Listeria monocytogenes-infected dendritic cells in the context of Tim-3 blockade

In this study, we engineered Listeria monocytogens (Lm) by deleting the LmΔactA/ΔinlB virulence determinants and inserting HCV-NS5B consensus antigens to develop a therapeutic vaccine against hepatitis C virus (HCV) infection. We tested this recombinant Lm-HCV vaccine in triggering of innate and ada...

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Published in:	PloS one Vol. 9; no. 1; p. e87821
Main Authors:	Ma, Cheng J, Ren, Jun P, Li, Guang Y, Wu, Xiao Y, Brockstedt, Dirk G, Lauer, Peter, Moorman, Jonathan P, Yao, Zhi Q
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 2014 Public Library of Science (PLoS)
Subjects:	Adaptive immunity Antigen presentation Antigens CD8 antigen CD8-Positive T-Lymphocytes - immunology Cytokines Cytotoxicity Dendritic cells Dendritic Cells - immunology Female Hepacivirus - genetics Hepacivirus - immunology Hepatitis Hepatitis A Virus Cellular Receptor 2 Hepatitis C Hepatitis C virus Hepatitis C, Chronic - genetics Hepatitis C, Chronic - immunology Hepatitis C, Chronic - prevention & control Humans Immune response Immune system Immunology Immunotherapy Infections Infectious diseases Interferon Internal medicine Listeria Listeria monocytogenes Listeria monocytogenes - genetics Listeria monocytogenes - immunology Listeriosis - genetics Listeriosis - immunology Lymphocytes Lymphocytes T Male Medicine Membrane Proteins - immunology Signal Transduction - immunology Signaling Th1 Cells - immunology Vaccines Veterans Viral Hepatitis Vaccines - genetics Viral Hepatitis Vaccines - immunology Viral infections Virulence Viruses United States > US Tennessee California
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Summary:	In this study, we engineered Listeria monocytogens (Lm) by deleting the LmΔactA/ΔinlB virulence determinants and inserting HCV-NS5B consensus antigens to develop a therapeutic vaccine against hepatitis C virus (HCV) infection. We tested this recombinant Lm-HCV vaccine in triggering of innate and adaptive immune responses in vitro using immune cells from HCV-infected and uninfected individuals. This live-attenuated Lm-HCV vaccine could naturally infect human dendritic cells (DC), thereby driving DC maturation and antigen presentation, producing Th1 cytokines, and triggering CTL responses in uninfected individuals. However, vaccine responses were diminished when using DC and T cells derived from chronically HCV-infected individuals, who express higher levels of inhibitory molecule Tim-3 on immune cells. Notably, blocking Tim-3 signaling significantly improved the innate and adaptive immune responses in chronically HCV-infected patients, indicating that novel strategies to enhance the potential of antigen presentation and cellular responses are essential for developing an effective therapeutic vaccine against HCV infection.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Competing Interests: Drs. Brockstedt and Lauer are employees of Aduro BioTech, Inc. The Listeria strain used in this study is patented as follows: Relevant U.S. patents: 8,287,883 Listeria attenuated for entry into non-phagocytic cells, vaccines comprising the Listeria, and methods of use thereof Inventors: Dubensky, Jr.; Thomas W. (Piedmont, CA), Brockstedt; Dirk G. (Richmond, CA), Cook; David N. (Lafayette, CA) 7,935,804 Engineered Listeria and methods of use thereof Inventors: Dubensky, Jr.; Thomas W. (Piedmont, CA), Skoble; Justin (Berkeley, CA), Lauer; Peter M. (Berkeley, CA), Cook; David N. (Lafayette, CA) 7,842,289 Recombinant nucleic acid molecules, expression cassettes, and bacteria, and methods of use thereof Inventors: Dubensky, Jr.; Thomas W. (Piedmont, CA), Portnoy; Daniel A. (Albany, CA), Luckett, Jr.; William S. (Richmond, CA), Cook; David N. (Lafayette, CA) 7,691,393 Listeria attenuated for entry into non-phagocytic cells, vaccines comprising the Listeria, and methods of use thereof Inventors: Dubensky, Jr.; Thomas W. (Piedmont, CA), Brockstedt; Dirk G. (Oakland, CA), Cook; David N. (Lafayette, CA). This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. Conceived and designed the experiments: ZQY JPM. Performed the experiments: CJM JPR GYL. Analyzed the data: CJM. Contributed reagents/materials/analysis tools: DGB PL. Wrote the paper: ZQY JPM. Lab management and reagent supply: XYW. Current address: Center of Infectious Diseases, Beijing Ditan Hospital Captial Medical University, Beijing, China
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0087821