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Cited by 83Virus-based gene therapy researchImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

The Balance between CD8(+) T Cell-Mediated Clearance of AAV-Encoded Antigen in the Liver and Tolerance Is Dependent on the Vector Dose

Open access
Kumar, Sandeep R.P., Hoffman, Brad E., Terhorst, Cox, de Jong, Ype P., Herzog, Roland W.·2017·Molecular Therapy
DOI 10.1016/j.ymthe.2017.02.014PMC PMC5383644
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Abstract

The liver continuously receives antigens from circulation and the gastrointestinal tract. A complex immune regulatory system has evolved in order to both limit inflammation and promote tolerance in the liver. Although in situ immune tolerance mechanisms enable successful gene therapy and liver transplantation, at the same time they facilitate chronic infections by pathogens such as hepatitis viruses. It is, however, poorly understood why hepatocytes infected with hepatitis viruses or transduced with adeno-associated virus (AAV)-based vectors may be rejected by CD8 + T cells several months later. We found that hepatic transfer of limited doses of an AAV-ovalbumin vector rapidly induced antigen-specific CD8 + T cells that only became functionally competent after >2 months. At this time, CD8 + T cells had downregulated negative checkpoint markers, e.g., the programmed death 1 [PD-1] receptor, and upregulated expression of relevant cytokines. At further reduced vector dose, only intrahepatic rather than systemic CD8 + T cell responses occurred, showing identical delay in antigen clearance. In contrast, PD-1-deficient mice rapidly cleared ovalbumin. Interestingly, higher vector dose directed sustained transgene expression without CD8 + T cell responses. Regulatory T cells, IL-10 expression, and Fas-L contributed to high-dose tolerance. Thus, viral vector doses profoundly impact CD8 + T cell responses.

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Crossref · 10.1016/j.ymthe.2017.02.014

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  • Initial priming of CD8+ T cells in the hepatic environment would explain the delayed functionality of the response previously documented in the C57BL/6-OVA model and in hemophilia A mice responding to FVIII.

    “Initial priming of CD8+ T cells in the hepatic environment would explain the delayed functionality of the response that we previously documented in both the C57BL/6-OVA model and in hemophilia A mice responding to FVIII.15,37”

    From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [15]

  • Increased levels of gene expression resulting from higher vector doses promote immune tolerance through elevated expression of IL-10, enhanced apoptosis of effector T cells, and enhanced Treg induction.

    “However, the exact opposite is true, and increased levels of gene expression resulting from higher vector doses promote immune tolerance through elevated expression of the immune suppressive cytokine IL-10, enhanced apoptosis of effector T cells, and enhanced Treg induction similar to that observed with a very high HBV inoculum in chimpanzees.15,56,57,58,59,60,61,62”

    From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [15]

  • Low-dose AAV8 gene transfer to the livers of C57BL/6 mice can trigger a CD8+ T cell response against OVA that, over time, acquires functionality and eliminates transgene expression in hepatocytes.

    “In one such example, we previously demonstrated that low-dose AAV8 gene transfer to the livers of C57BL/6 mice can trigger a CD8+ T cell response against the model antigen ovalbumin (OVA) that, over time, acquires functionality and eliminates transgene expression in hepatocytes.15”

    From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [15]

  • Priming of T cells in the hepatic environment induces a response that is initially not fully functional and thus fails to eliminate transgene expression until several weeks to months later unless the PD1-PDL1 checkpoint is disrupted.

    “However, priming of T cells in the hepatic environment induces a response that is initially not fully functional and thus fails to eliminate transgene expression until several weeks to months later unless the PD1-PDL1 checkpoint is disrupted.15”

    From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [15]

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Authors
Kumar, S. R. P., Hoffman, B. E., Terhorst, C., de Jong, Y. P., & Herzog, R. W.
Affiliations
  • University of Florida (US)
  • Harvard University (US)
Corresponding author
Herzog, Roland W.
ORCID
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2017-04
Volume
25
Issue
4
Pages
880-891
ISSN
1525-0016 (ISSN-L)
DOI
10.1016/j.ymthe.2017.02.014
PMC
PMC5383644
OpenAlex
W2592177978
Cited by
83
References
74
Citations by year
2026: 10 · 2025: 8 · 2024: 12 · 2023: 10 · 2022: 3 · 2021: 12 · 2020: 8 · 2019: 10 · 2018: 6 · 2017: 4
FWCI
5.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (R01 AI51390, R01 HL097088, R01 HL131093)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
adeno-associated virus vectors, CD8+ T cells, liver tolerance, vector dose, ovalbumin, PD-1, regulatory T cells, IL-10, Fas ligand, hepatocyte transduction, gene therapy, chronic viral infection, antigen clearance
MeSH terms
Dependovirus, Animals, Antigens, Viral, Genetic Vectors, Immune Tolerance, Liver, Male, Memory, Phenotype, Transduction, Genetic, Signal Transduction, Gene Expression, Cytokines, Gene Transfer Techniques, CD8-Positive T-Lymphocytes, T-Cell Antigen Receptor Specificity, Mice, B7-H1 Antigen, Programmed Cell Death 1 Receptor

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