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 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.
Department of Internal Medicine, Division of Infectious Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
Cheng J
CJ
Ma
Department of Internal Medicine, Division of Infectious Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
Jun P
JP
Ren
Department of Internal Medicine, Division of Infectious Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
Guang Y
GY
Li
Department of Internal Medicine, Division of Infectious Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
Xiao Y
XY
Wu
Aduro BioTech, Inc. Berkeley, California, United States of America.
Dirk G
DG
Brockstedt
Aduro BioTech, Inc. Berkeley, California, United States of America.
Peter
P
Lauer
Hepatitis (HCV/HIV) Program, Department of Veterans Affairs, James H. Quillen VA Medical Center, Johnson City, Tennessee, United States of America ; Department of Internal Medicine, Division of Infectious Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
Jonathan P
JP
Moorman
Hepatitis (HCV/HIV) Program, Department of Veterans Affairs, James H. Quillen VA Medical Center, Johnson City, Tennessee, United States of America ; Department of Internal Medicine, Division of Infectious Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
Zhi Q
ZQ
Yao
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology*; D008088:Listeriosis / Q000235:genetics / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014761:Viral Hepatitis Vaccines / Q000235:genetics / Q000276:immunology*
C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D014761:Viral Hepatitis Vaccines