Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver
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UNLABELLED: The mechanisms of tolerance in the liver that limit susceptibility to food allergy and that mediate the acceptance of liver transplants, even with a complete major histocompatibility complex (MHC) mismatch, remain poorly defined. Here we report that in a model of liver-directed gene transfer, cytotoxic T lymphocyte (CTL) responses to non-self antigens are controlled by hepatic regulatory T cells (Tregs) that secrete the immunosuppressive cytokine interleukin (IL)-10 in response to the antigen. In addition, Kupffer cells (KCs), normally thought to initiate immune responses, are rendered tolerogenic in this context. The depletion of KCs results in a complete abrogation of IL-10 production by hepatic Tregs, indicating an interaction between Tregs and KCs in the induction of tolerance. CONCLUSION: Our study suggests that hepatic Tregs together with KCs create a local suppressive microenvironment that prevents the establishment of the CTL response. These mechanisms provide pivotal insights and may prove instrumental in the tolerization toward non-self therapeutic proteins delivered to the liver.
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Mouse studies have shown liver-directed AAV gene therapy results in tolerogenic responses by the induction of Tregs.
“mouse studies have shown liver-directed AAV gene therapy results in tolerogenic responses by the induction of Tregs,52, 53, 54, 55, 56, 57, 58, 59”
From Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells (2021) · cites this paper as [57]
Tregs have been implicated in contributing to long-term transgene expression in preclinical studies and clinical trials.
“have been implicated in contributing to long-term transgene expression in preclinical studies (35, 160, 161) and clinical trials (162 -164).”
From A versatile toolkit for overcoming AAV immunity (2022) · cites this paper as [161]
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 [57]
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References 37 · Cited by 237
- Authors
- Breous, E., Somanathan, S., Vandenberghe, L. H., & Wilson, J. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Wilson, James M.
- Venue
- Hepatology
- Published
- 2009-08
- Volume
- 50
- Issue
- 2
- Pages
- 612-621
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC4380144
- OpenAlex
- W1965696997
- Cited by
- 237
- References
- 37
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 14 · 2023: 10 · 2022: 13 · 2021: 22 · 2020: 17 · 2019: 13 · 2018: 15 · 2017: 20 · 2016: 14 · 2015: 16 · 2014: 16 · 2013: 20 · 2012: 8
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01 HL 59407, P01HL059407)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK 47757, P30DK047757)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01 HD57247, P01HD057247)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- Kupffer cells, liver-directed gene transfer, IL-10, cytotoxic T lymphocyte response, liver transplantation, MHC mismatch, food allergy
- MeSH terms
- alpha 1-Antitrypsin, Animals, Cells, Cultured, Humans, Immune Tolerance, Kupffer Cells, Liver, Male, Mice, Inbred C57BL, Mice, Transgenic, Interleukin-10, T-Lymphocytes, Regulatory, Mice
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