Enhanced Virus-Specific CD8+ T Cell Responses by Listeria monocytogenes-Infected Dendritic Cells in the Context of Tim-3 Blockade |
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| Authors: | Cheng J. Ma Jun P. Ren Guang Y. Li Xiao Y. Wu Dirk G. Brockstedt Peter Lauer Jonathan P. Moorman Zhi Q. Yao |
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| Affiliation: | 1. Hepatitis (HCV/HIV) Program, Department of Veterans Affairs, James H. Quillen VA Medical Center, Johnson City, Tennessee, United States of America.; 2. Department of Internal Medicine, Division of Infectious Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.; 3. Aduro BioTech, Inc. Berkeley, California, United States of America.; University of Montreal, Canada, |
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| Abstract: | 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. |
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