Regulatory T cells and TLR9 activation shape antibody formation to a secreted transgene product in AAV muscle gene transfer
Open accessAbstract
Adeno-associated viral (AAV) gene delivery to skeletal muscle is being explored for systemic delivery of therapeutic proteins. To better understand the signals that govern antibody formation against secreted transgene products in this approach, we administered an intramuscular dose of AAV1 vector expressing human coagulation factor IX (hFIX), which does not cause antibody formation against hFIX in C57BL/6 mice. Interestingly, co-administration of a TLR9 agonist (CpG-deoxyoligonucleotide, ODN) but not of lipopolysaccharide, caused a transient anti-hFIX response. ODN activated monocyte-derived dendritic cells and enhanced T follicular helper cell responses. While depletion of regulatory T cells (Tregs) also caused an antibody response, TLR9 activation combined with Treg depletion instead resulted in prolonged CD8+ T cell infiltration of transduced muscle. Thus, Tregs modulate the response to the TLR9 agonist. Further, Treg re-population eventually resolved humoral and cellular immune responses. Therefore, specific modes of TLR9 activation and Tregs orchestrate antibody formation in muscle gene transfer.
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moDCs have been implicated in activation of T follicular helper T cells in the mouse model of muscle gene transfer.
“or activation of T follicular helper T cells in the mouse model of muscle gene transfer (47, 48).”
From Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood (2022) · cites this paper as [48]
TLR9 sensing of AAV vector genomes is required for anti-capsid CD8+ T cell responses.
“Importantly, TLR9 sensing of AAV vector genomes has been shown to be required for anti-capsid CD8+ T cell responses (9–14).”
From Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene Therapy (2021) · cites this paper as [10]
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Mandal, S., & Tiwari, P. K. (2020) · Advances in medical diagnosis, treatment, and care (AMDTC) book series · doi:10.4018/978-1-7998-6530-8.ch004 · Cited by 2 · see citing works
Gene Therapy and Gene Editing for Cancer Therapeutics
Mandal, S., & Tiwari, P. K. (2023) · IGI Global eBooks · doi:10.4018/979-8-3693-3026-5.ch033 · Cited by 2 · see citing works
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Detection of Humoral Response to Transgene Protein and Gene Editing Reagents
Buchlis, G., & Gorovits, B. (2024) · Wiley eBooks · doi:10.1002/9781119852810.ch12 · Cited by 1 · see citing works
Host Endoplasmic Reticulum Stress and Interferon Responses Contribute to AAV-Induced Ocular ToxicityPreprint
Gardner, A., Hong, C. M., Zhao, S. R., Daniels, A., & Cepko, C. L. (2026) · eLife · doi:10.7554/elife.111783
Host Endoplasmic Reticulum Stress and Interferon Responses Contribute to AAV-Induced Ocular ToxicityPreprint
Gardner, A., Hong, C. M., Zhao, S. R., Daniels, A., & Cepko, C. L. (2026) · eLife · doi:10.7554/elife.111783.1
- Authors
- Herzog, R. W., Cooper, M., Perrin, G. Q., Biswas, M., Martino, A. T., Morel, L., Terhorst, C., & Hoffman, B. E.
- Affiliations
- University of Florida Health (US)
- University of Florida (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Herzog, Roland W.
- Hoffman, Brad E.
- Venue
- Cellular Immunology
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 342
- Pages
- 103682
- ISSN
- 0008-8749 (ISSN-L)
- PMC
- PMC5794662
- OpenAlex
- W2739915030
- Cited by
- 39
- References
- 55
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 9 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 2
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cellular Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Pfizer
- National Institutes of Health (R01 HL131093, R01 AI51390)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- regulatory T cells, TLR9 activation, CpG oligodeoxynucleotides, adeno-associated virus, AAV gene transfer, skeletal muscle, coagulation factor IX, antibody response, T follicular helper cells, dendritic cells, CD8+ T cell infiltration, immune tolerance
- MeSH terms
- Dependovirus, Animals, Antibody Formation, Factor IX, Male, Mice, Inbred C57BL, Oligodeoxyribonucleotides, Gene Transfer Techniques, Muscle, Skeletal, Transgenes, T-Lymphocytes, Regulatory, Toll-Like Receptor 9, Mice
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