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 cells have full access to hepatocellular antigens, which functionally act as a secondary lymphoid organ for CD8+ T cell priming.
“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]
The Introduction and the section on competition between liver and lymph nodes (pages unavailable) show that naive CD8+ T cells can access antigen in the liver and undergo primary activation there. But the Discussion says liver priming produces ineffective CTL function and reduced T-cell survival, unlike lymph-node priming. The paper therefore supports intrahepatic priming, not the unqualified claim that the liver functionally acts as a secondary lymphoid organ. (LLM, conf=0.86)
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The p-i Concept: Pharmacological Interaction of Drugs With Immune Receptors
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Heart Transplantation: Challenges Facing the FieldPreprint
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Novel Aspects of the Liver Microenvironment in Hepatocellular Carcinoma Pathogenesis and Development
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Self-citationCell-mediated rejection results in allograft loss after liver cell transplantation
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Viral triggers for autoimmunity: Is the ‘glass of molecular mimicry’ half full or half empty?
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Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Status and Novel Perspectives
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Hepatic sinusoidal cells in health and disease: update from the 14th International Symposium
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Coinhibitory receptors and CD8 T cell exhaustion in chronic infections
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Virally Infected Mouse Liver Endothelial Cells Trigger CD8+ T-Cell Immunity
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A look behind closed doors: interaction of persistent viruses with dendritic cells
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Rational design and evaluation of HBsAg polymeric nanoparticles as antigen delivery carriers
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Differential priming of CD8 and CD4 T-cells in animal models of autoimmune hepatitis and cholangitis
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Immunology of the gut and liver: a love/hate relationship
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Developments in cancer vaccines for hepatocellular carcinoma
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The role of liver sinusoidal cells in local hepatic immune surveillance
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Influence of genes, sex, age and environment on the onset of autoimmune hepatitis
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Specific CD8+T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis
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Checkpoint Inhibitors and Therapeutic Vaccines for the Treatment of Chronic HBV Infection
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The liver as a central "hub" of the immune system: pathophysiological implications
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Combinatorial immunotherapy strategies for hepatocellular carcinoma
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Therapeutic strategies for a functional cure of chronic hepatitis B virus infection
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Self-citationCD4 T cells in hepatic immune tolerance
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Priming and Maintenance of Adaptive Immunity in the Liver
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Immune outcomes in the liver: Is CD8 T cell fate determined by the environment?
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Organ-specific Differences in Achieving Tolerance
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Malaria and the liver: immunological hide-and-seek or subversion of immunity from within?
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- 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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