Nonlytic Lymphocytes Engineered to Express Virus-Specific T-Cell Receptors Limit HBV Infection by Activating APOBEC3
Standard
Nonlytic Lymphocytes Engineered to Express Virus-Specific T-Cell Receptors Limit HBV Infection by Activating APOBEC3. / Koh, Sarene; Kah, Janine; Tham, Christine Y L; Yang, Ninghan; Ceccarello, Erica; Chia, Adeline; Chen, Margaret; Khakpoor, Atefeh; Pavesi, Andrea; Tan, Anthony T; Dandri, Maura; Bertoletti, Antonio.
In: GASTROENTEROLOGY, Vol. 155, No. 1, 07.2018, p. 180-193.e6.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Nonlytic Lymphocytes Engineered to Express Virus-Specific T-Cell Receptors Limit HBV Infection by Activating APOBEC3
AU - Koh, Sarene
AU - Kah, Janine
AU - Tham, Christine Y L
AU - Yang, Ninghan
AU - Ceccarello, Erica
AU - Chia, Adeline
AU - Chen, Margaret
AU - Khakpoor, Atefeh
AU - Pavesi, Andrea
AU - Tan, Anthony T
AU - Dandri, Maura
AU - Bertoletti, Antonio
N1 - Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
PY - 2018/7
Y1 - 2018/7
N2 - BACKGROUND & AIMS: Strategies to develop virus-specific T cells against hepatic viral infections have been hindered by safety concerns. We engineered nonlytic human T cells to suppress replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) without overt hepatotoxicity and investigated their antiviral activity.METHODS: We electroporated resting T cells or T cells activated by anti-CD3 with mRNAs encoding HBV or HCV-specific T-cell receptors (TCRs) to create 2 populations of TCR-reprogrammed T cells. We tested their ability to suppress HBV or HCV replication without lysis in 2-dimensional and 3-dimensional cultures of HepG2.2.15 cells and HBV-infected HepG2-hNTCP cells. We also injected TCR-reprogrammed resting and activated T cells into HBV-infected urokinase-type plasminogen activator/severe combined immunodeficiency disease/interleukin 2γ mice with humanized livers and measured levels of intrahepatic and serological viral parameters and serum alanine aminotransferase. Livers were collected for analysis of gene expression patterns to determine effects of the TCR-reprogrammed T cells.RESULTS: TCR-reprogrammed resting T cells produced comparable levels of interferon gamma but lower levels of perforin and granzyme than activated T cells and did not lyse HCV- or HBV-infected hepatoma cells. Although T-cell secretion of interferon gamma was required to inhibit HCV replication, the HBV-specific TCR-reprogrammed resting T cells reduced HBV replication also through intracellular activation of apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3). The mechanism of APOBEC3 intracellular activation involved temporal expression of lymphotoxin-β receptor ligands on resting T cells after TCR-mediated antigen recognition and activation of lymphotoxin-β receptor in infected cells.CONCLUSIONS: We developed TCR-reprogrammed nonlytic T cells capable of activating APOBEC3 in hepatoma cells and in HBV-infected human hepatocytes in mice, limiting viral infection. These cells with limited hepatotoxicity might be developed for treatment of chronic HBV infection.
AB - BACKGROUND & AIMS: Strategies to develop virus-specific T cells against hepatic viral infections have been hindered by safety concerns. We engineered nonlytic human T cells to suppress replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) without overt hepatotoxicity and investigated their antiviral activity.METHODS: We electroporated resting T cells or T cells activated by anti-CD3 with mRNAs encoding HBV or HCV-specific T-cell receptors (TCRs) to create 2 populations of TCR-reprogrammed T cells. We tested their ability to suppress HBV or HCV replication without lysis in 2-dimensional and 3-dimensional cultures of HepG2.2.15 cells and HBV-infected HepG2-hNTCP cells. We also injected TCR-reprogrammed resting and activated T cells into HBV-infected urokinase-type plasminogen activator/severe combined immunodeficiency disease/interleukin 2γ mice with humanized livers and measured levels of intrahepatic and serological viral parameters and serum alanine aminotransferase. Livers were collected for analysis of gene expression patterns to determine effects of the TCR-reprogrammed T cells.RESULTS: TCR-reprogrammed resting T cells produced comparable levels of interferon gamma but lower levels of perforin and granzyme than activated T cells and did not lyse HCV- or HBV-infected hepatoma cells. Although T-cell secretion of interferon gamma was required to inhibit HCV replication, the HBV-specific TCR-reprogrammed resting T cells reduced HBV replication also through intracellular activation of apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3). The mechanism of APOBEC3 intracellular activation involved temporal expression of lymphotoxin-β receptor ligands on resting T cells after TCR-mediated antigen recognition and activation of lymphotoxin-β receptor in infected cells.CONCLUSIONS: We developed TCR-reprogrammed nonlytic T cells capable of activating APOBEC3 in hepatoma cells and in HBV-infected human hepatocytes in mice, limiting viral infection. These cells with limited hepatotoxicity might be developed for treatment of chronic HBV infection.
KW - Animals
KW - Cytidine Deaminase
KW - Cytosine Deaminase/immunology
KW - Electroporation
KW - Hep G2 Cells
KW - Hepacivirus/immunology
KW - Hepatitis B virus/immunology
KW - Hepatitis B, Chronic/therapy
KW - Hepatocytes
KW - Humans
KW - Interferon-gamma/immunology
KW - Liver/metabolism
KW - Lymphocyte Activation/immunology
KW - Mice
KW - Mice, SCID
KW - RNA, Messenger
KW - RNA, Viral
KW - Receptors, Antigen, T-Cell/genetics
KW - T-Lymphocytes/immunology
U2 - 10.1053/j.gastro.2018.03.027
DO - 10.1053/j.gastro.2018.03.027
M3 - SCORING: Journal article
C2 - 29550589
VL - 155
SP - 180-193.e6
JO - GASTROENTEROLOGY
JF - GASTROENTEROLOGY
SN - 0016-5085
IS - 1
ER -
