Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity
David G. Bowen, … , Geoffrey W. McCaughan, Patrick Bertolino
David G. Bowen, … , Geoffrey W. McCaughan, Patrick Bertolino
Published September 1, 2004
Citation Information: J Clin Invest. 2004;114(5):701-712. https://doi.org/10.1172/JCI21593.
View: Text | PDF
Article Immunology

The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity

  • Text
  • PDF
Abstract

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.

Authors

David G. Bowen, Monica Zen, Lauren Holz, Thomas Davis, Geoffrey W. McCaughan, Patrick Bertolino

×

Figure 7

Options: View larger image (or click on image) Download as PowerPoint
CD8+ Des-TCR T cells activated within the liver exhibited defective CTL ...
CD8+ Des-TCR T cells activated within the liver exhibited defective CTL function. (A) Representative histograms of CD43 activation–associated glycoform expression by CD8+ Des-TCR cells in livers of Met-Kb mice treated with anti-CD62L (thin line) or control IgG (thick line). Organs were harvested 2.5 days after transfer of Des-TCR LN cells. (B) CTL activity of CD8+ Des-TCR cells harvested from the livers of Met-Kb mice treated with anti-CD62L (open squares) or control IgG (filled squares) toward P815-Kb target cells at 2.5 days after transfer. The effector/target (E/T) ratio was calculated by determination of the exact number of transgenic T cells present in the well. CTL activity toward P815 control target cells was not detected (data not shown). (C and D) Representative CD43 activation–associated glycoform histograms (C) and CFSE profiles (D) of CD8+ Des-TCR cells from the livers of Alb-Kb (H-2Kdk) (thin line) and Met-Kb (H-2Kdk) mice (thick line). Organs were harvested 6 days after transfer of Des-TCR (H-2Kdk) LN cells, and lymphocytes were prepared and analyzed by FACS. All plots were gated on forward and side scatter gates appropriate for lymphocytes and CD8+ Des-TCR+ PI– cells. (E) CTL activity of CD8+ Des-TCR cells harvested from the livers and LNs of Alb-Kb (H-2Kdk) (round symbols) and Met-Kb (H-2Kdk) mice (square symbols) incubated with P815 (open symbols) or P815-Kb target cells (filled symbols). Organs were harvested 6 days after transfer of Des-TCR (H-2Kdk) LN cells. The effector/target ratio was calculated by determination of the exact number of transgenic T cells present in each well.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts