The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.
Plasmacytoid and conventional dendritic cells cooperate in crosspriming AAV capsid-specific CD8+ T cells
Open accessAbstract
Key Points: Crosspriming of AAV capsid-specific CD8+ T cells requires cooperation between distinct subsets of DCs. Innate immune sensing of the viral DNA genome induces cross-presentation of viral capsid in trans.
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Despite evidence for various innate responses to AAV, the existence of other pathways leading to antigen-specific T cell responses has been unknown.24,25,43,44,45”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“all of the AAV-induced cytokines and chemokines can be upregulated by activation of TLR9 in the periphery using synthetic CpG-rich oligonucleotides.8,9,10,11,12,52,53,54,55,56,57,58”
From An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission (2024) · cites this paper as [11]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA”
From Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses (2021) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“Plasmacytoid dendritic cells (pDCs) are critical for mounting a TLR9/MyD88-dependent early innate immune response to AAV vectors (15) and they subsequently orchestrate anti-capsid CD8+ T cell responses in vivo by activating conventional DCs to cross-present capsid antigen (18).”
From Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses (2021) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“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 [9]
In the citing paper
“Furthermore, the TLR9/MyD88 pathway is not only vital for mounting a CD8+ T-cell response against the AAV capsid but also liver and muscle-directed transgenes [28, 34, 35, 41].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [28]
In the citing paper
“Adaptive anti-capsid humoral [27] and cytotoxic [28, 29] immune responses have been shown to be restricted in vivo by inhibiting innate immune activation pathways.”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [28]
In the citing paper
“Studies suggest that cooperation between plasmacytoid DCs, conventional DCs, and CD4+ T cells results in cross-presentation of AAV particles on MHC I, and, subsequently, activation of CD8+ T cells [28, 29].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [28]
In the citing paper
“Capsid-specific CD8+ T cells expand and potentially clear AAV transduced cells, which results in loss of transgene expression and inflammation of target organs [59, 60].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [60]
In the citing paper
“but did not participate directly in CD8+ T cell priming (42).”
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 [42]
In the citing paper
“In mice, cDCs were shown to play a role in priming of a cytotoxic T cell response against immunogenic ovalbumin peptide inserted into the AAV2 capsid protein sequence (42).”
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 [42]
In the citing paper
“More recent work has highlighted the role of innate immune system in response to AAV therapeutics (42–46)”
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 [42]
In the citing paper
“Indeed, both TLR9 and T1 IFNs (and also CD4+ T help) are requisite for anti-capsid CD8+ T cell priming (9, 15).”
From Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene Therapy (2021) · cites this paper as [9]
In the citing paper
“T1 IFN along with CD4+ T cell help contributes to licensing of cDCs, which then prime capsid specific CD8+ T cells (9, 15).”
From Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene Therapy (2021) · cites this paper as [9]
In the citing paper
“Another limitation is that CpG depletion does not eliminate antibody formation against the capsid or transgene product, which can be modified by but does not depend on the TLR9-MyD88 pathway (9, 12, 15).”
From Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene Therapy (2021) · cites this paper as [9]
In the citing paper
“However, it should be pointed out that even TLR9 deficient mice do not show complete abolishment of CD8+ T cell responses, as our current and published studies have shown (7–9).”
From Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene Therapy (2021) · cites this paper as [9]
In the citing paper
“However, adaptive immune responses to the capsid were found to be independent of TLR2 in a murine model of muscle gene transfer.”
From Innate immune sensing of adeno-associated virus vectors (2024) · cites this paper as [26]
In the citing paper
“Thus far, a strong dependency of immune responses to AAV gene transfer on TLR2 has not been documented.”
From Innate immune sensing of adeno-associated virus vectors (2024) · cites this paper as [26]
In the citing paper
“Several other studies showed no effect of STING deficiency on B or T cell responses.”
From Innate immune sensing of adeno-associated virus vectors (2024) · cites this paper as [26]
In the citing paper
“Sensing of the AAV genome by TLR9 in plasmacytoid dendritic cells (pDCs) conditions conventional cross-presenting dendritic cells (cDCs) via IFN-I to prime AAV capsid-specific CD8+ T cells.17,24,25,26”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [25]
In the citing paper
“In this regard, the requirements are similar to those for MHC class I presentation of AAV capsid antigen.25,41”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [25]
In the citing paper
“In lymphoid organs, anti-viral responses may be orchestrated by migration of pDCs and XCR1+ DCs to sites of virally infected APCs, where they co-cluster, allowing pDCs to condition XCR1+ DCs through IFN-I.25,26”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [25]
In the citing paper
“CD8+ T cell responses against input capsid may develop faster in mice than against the transgene product.25,65”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [25]
In the citing paper
“XCR1+ cDCs closely cooperate with pDCs in cross-priming of CD8+ T cells, with pDCs conditioning the XCR1+ cDCs with cytokines.25,26,35”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [25]
In the citing paper
“However, this does not apply here because AAV8 does not elicit a CD8+ T cell response against capsid in mice and because the vector dose was anyhow too low to generate such a response.25,66,67”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [25]
In the citing paper
“Cross-priming of anti-viral CD8+ T cell responses following TLR9 activation in pDCs requires IFNAR expression in cDCs.25”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [25]
In the citing paper
“Previous work had identified TLR9, which recognizes unmethylated CpG sequences present in viral or bacterial but not mammalian DNA, as the sensor involved in the induction of type I IFN responses in pDCs 20,22 .”
From AAV vectors trigger DNA damage response-dependent pro-inflammatory signalling in human iPSC-derived CNS models and mouse brain (2025) · cites this paper as [20]
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Citations
Cites
1 retracted
Jayandharan, G. R., Aslanidi, G., Martino, A. T., Jahn, S. C., Perrin, G. Q., Herzog, R. W., & Srivastava, A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1012753108 · Cited by 72
Self-citationRetractedToll-like receptors and their crosstalk with other innate receptors in infection and immunity
Kawai, T., & Akira, S. (2011) · Immunity · doi:10.1016/j.immuni.2011.05.006 · Cited by 3,658
Manno, C. S., Pierce, G. F., Arruda, V. R., Glader, B., Ragni, M., Rasko, J. J. E., Ozelo, M. C., Hoots, K., Blatt, P., Konkle, B., et al. (2006) · Nature Medicine · doi:10.1038/nm1358 · Cited by 2,163
Jung, S., Unutmaz, D., Wong, P., Sano, G., Santos, K. D. L., Sparwasser, T., Wu, S., Vuthoori, S., Ko, K., Zavala, F., et al. (2002) · Immunity · doi:10.1016/s1074-7613(02)00365-5 · Cited by 1,953
Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B
Nathwani, A. C., Tuddenham, E. G. D., Rangarajan, S., Rosales, C., McIntosh, J., Linch, D. C., Chowdary, P., Riddell, A., Pie, A. J., Harrington, C., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1108046 · Cited by 1,864
Self-citationLong-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B
Nathwani, A. C., Reiss, U. M., Tuddenham, E. G. D., Rosales, C., Chowdary, P., McIntosh, J., Della Peruta, M., Lheriteau, E., Patel, N., Raj, D., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1407309 · Cited by 1,273
Self-citationTherapeutic in vivo gene transfer for genetic disease using AAV: Progress and challenges
Mingozzi, F., & High, K. A. (2011) · Nature Reviews Genetics · doi:10.1038/nrg2988 · Cited by 893
Zhong, L., Li, B., Mah, C. S., Govindasamy, L., Agbandje-McKenna, M., Cooper, M., Herzog, R. W., Zolotukhin, I., Warrington, K. H., Weigel-Van Aken, K. A., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802866105 · Cited by 558
Self-citationBennett, J., Wellman, J., Marshall, K. A., McCague, S., Ashtari, M., DiStefano-Pappas, J., Elci, O. U., Chung, D. C., Sun, J., Wright, J. F., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)30371-3 · Cited by 461
Gaudet, D., Méthot, J., Déry, S., Brisson, D., Essiembre, C., Tremblay, G., Tremblay, K., de Wal, J., Twisk, J., van den Bulk, N., et al. (2013) · Gene Therapy · doi:10.1038/gt.2012.43 · Cited by 404
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Reizis, B. (2019) · Immunity · doi:10.1016/j.immuni.2018.12.027 · Cited by 702
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Metadata
- Authors
- Rogers, G. L., Shirley, J. L., Zolotukhin, I., Kumar, S. R. P., Sherman, A., Perrin, G. Q., Hoffman, B. E., Srivastava, A., Basner-Tschakarjan, E., Wallet, M. A., Terhorst, C., Biswas, M., & Herzog, R. W.
- Affiliations
- University of Florida Health (US)
- Center of Molecular and Cellular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA;
- University of Florida (US)
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2017-06-15
- Volume
- 129
- Issue
- 24
- Pages
- 3184-3195
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC5472899
- OpenAlex
- W2610861971
- Semantic Scholar
- e6cfb89e4d66a95c980f78792a7ed364f7e69294
- Cited by
- 131
- References
- 60
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 16 · 2023: 17 · 2022: 15 · 2021: 19 · 2020: 7 · 2019: 15 · 2018: 11 · 2017: 4
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-097088, HL131093, R01HL097088, R01HL131093)
- National Institute of Allergy and Infectious Diseases (R01AI051390, R01 AI51390, T32AI007110)
- National Institute of Diabetes and Digestive and Kidney Diseases (UC4DK104194)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- plasmacytoid dendritic cells, myeloid dendritic cells, cross-presentation, AAV capsid, CD8+ T cells, viral DNA sensing, innate immunity
- MeSH terms
- Dependovirus, Animals, Dendritic Cells, Lymphocyte Activation, Plasma Cells, Genetic Therapy, Mice, Knockout, CD8-Positive T-Lymphocytes, Capsid Proteins, Toll-Like Receptor 9, Mice, Myeloid Differentiation Factor 88
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