Heterologous T cells can help restore function in dysfunctional hepatitis C virus nonstructural 3/4A-specific T cells during therapeutic vaccination

The hepatitis C virus (HCV)-specific T cell response in patients with chronic HCV is dysfunctional. In this study, we aimed at restoring immunological function through therapeutic vaccination in a transgenic mouse model with impaired HCV-specific T cell responses due to a persistent presence of hepa...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2011-05, Vol.186 (9), p.5107-5118
Main Authors: Chen, Antony, Ahlén, Gustaf, Brenndörfer, Erwin D, Brass, Anette, Holmström, Fredrik, Chen, Margaret, Söderholm, Jonas, Milich, David R, Frelin, Lars, Sällberg, Matti
Format: Article
Language:English
Subjects:
Animal
Animals
Animals, Genetically Modified
Antigens
Antigens, Viral - immunology
Antigens, Viral - therapeutic use
Blotting
Blotting, Western
Cell Line
Cell Line, Tumor
Chronic
Disease Models
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Genetically Modified
Hepacivirus
Hepacivirus - immunology
Hepatitis B Core Antigens
Hepatitis B Core Antigens - immunology
Hepatitis B Core Antigens - therapeutic use
Hepatitis C
Hepatitis C virus
Hepatitis C, Chronic - immunology
Hepatitis C, Chronic - therapy
Humans
Immunologi inom det medicinska området
immunology
Immunology in the medical area
Immunoprecipitation
Inbred BALB C
Inbred C57BL
Infectious Medicine
Infektionsmedicin
Lymphocyte Activation
Lymphocyte Activation - immunology
Medicin och hälsovetenskap
methods
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
T-Lymphocytes
T-Lymphocytes - immunology
therapeutic use
therapy
Transgenic
Tumor
Vaccination
Vaccination - methods
Viral
Viral Hepatitis Vaccines
Viral Hepatitis Vaccines - immunology
Viral Nonstructural Proteins
Viral Nonstructural Proteins - immunology
Western
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Summary:The hepatitis C virus (HCV)-specific T cell response in patients with chronic HCV is dysfunctional. In this study, we aimed at restoring immunological function through therapeutic vaccination in a transgenic mouse model with impaired HCV-specific T cell responses due to a persistent presence of hepatic HCV nonstructural (NS)3/4A Ags. The HCV-specific T cells have an actively maintained dysfunction reflected in reduced frequency, impaired cytokine production, and impaired effector function in vivo, which can be partially restored by blocking regulatory T cells or programmed cell death ligand 1. We hypothesized that the impairment could be corrected by including sequences that created a normal priming environment by recruiting "healthy" heterologous T cells and by activating innate signaling. Endogenously expressed hepatitis B core Ag (HBcAg) can recruit heterologous T cells and activate TLR (TLR7) signaling. Hence, by combining HCV NS3/4A with different forms of HBcAg we found that heterologous sequences somewhat improved activation and expansion of NS3/4A-specific T cells in a wild-type host. Importantly, the signals provided by HBcAg effectively restored the activation of HCV-specific T cells in a tolerant NS3/4A-transgenic mouse model. The adjuvant effect could also be transferred to the priming of dysfunctional HLA-A2-restricted NS3-specific T cells in vivo. Thus, recruiting healthy heterologous T cells to the site of priming may also help restore HCV-specific responses present in a chronically infected host.
ISSN:0022-1767
1550-6606
1550-6606
DOI:10.4049/jimmunol.1001790