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The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity
Open accessAbstract
Hepatic immunobiology is paradoxical: although the liver possesses unusual tolerogenic properties, it is also the site of effective immune responses against multiple pathogens and subject to immune-mediated pathology. The mechanisms underlying this dichotomy remain unclear. Following previous work demonstrating that the liver may act as a site of primary T cell activation, we demonstrate here that the balance between immunity and tolerance in this organ is established by competition for primary activation of CD8+ T cells between the liver and secondary lymphoid tissues, with the immune outcome determined by the initial site of activation. Using a transgenic mouse model in which antigen is expressed within both liver and lymph nodes, we show that while naive CD8+ T cells activated within the lymph nodes were capable of mediating hepatitis, cells undergoing primary activation within the liver exhibited defective cytotoxic function and shortened half-life and did not mediate hepatocellular injury. The implications of these novel findings may pertain not only to the normal maintenance of peripheral tolerance, but also to hepatic allograft tolerance and the immunopathogenesis of chronic viral hepatitis.
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“These results proved that circulating T 458 cells have full access to hepatocellular antigens, which functionally act as a secondary 459 lymphoid organ for CD8+ T cell priming(93-95).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [95]
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Metadata
- Authors
- Bowen, D. G., Zen, M., Holz, L., Davis, T., McCaughan, G. W., & Bertolino, P.
- Affiliations
- Centenary Institute (AU)
- Venue
- Journal of Clinical Investigation
- Published
- 2004-09-01
- Volume
- 114
- Issue
- 5
- Pages
- 701-712
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC514586
- OpenAlex
- W1968141301
- Cited by
- 316
- References
- 53
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 8 · 2022: 7 · 2021: 11 · 2020: 11 · 2019: 12 · 2018: 11 · 2017: 14 · 2016: 15 · 2015: 14 · 2014: 18 · 2013: 27 · 2012: 23
- FWCI
- 6.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Children’s Hospital of Wisconsin Research Institute
- University of Sydney
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- liver, CD8+ T cells, peripheral tolerance, secondary lymphoid organs, hepatitis, cytotoxic function, chronic viral hepatitis, transgenic mouse model
- MeSH terms
- Adjuvants, Immunologic, Animals, Antibodies, Monoclonal, Hepatitis, Immune Tolerance, Liver, Lymph Nodes, T-Lymphocytes, CD8-Positive T-Lymphocytes, L-Selectin, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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