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 ...
    • Pancreatic Cancer (Jul 2025)
    • 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)
    • 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 6

Options: View larger image (or click on image) Download as PowerPoint
Intrahepatic activation of CD8+ Des-TCR T cells was associated with redu...
Intrahepatic activation of CD8+ Des-TCR T cells was associated with reduced half-life. (A and B) Administration of anti-CD62L mAb to Met-Kb mice resulted in reduced CD8+ Des-TCR T cell numbers 2.5 and 6 days after adoptive transfer. Unmanipulated and splenectomized Met-Kb and B10.BR mice were preadministered anti-CD62L mAb or purified rat IgG as described in Methods. A further dose of antibodies was administered intraperitoneally 24 hours after adoptive transfer. Organs were harvested at day 2.5 (A) and day 6 (B), and lymphocytes were analyzed by flow cytometry. Cell numbers for blood represent CD8+ Des-TCR T cells/ml; cell numbers for other organs represent total CD8+ Des-TCR T cells from the organ. Total cell numbers represent the sum of CD8+ Des-TCR T cells retrieved from these organs. Plots represent means ± SEM for groups of 3 mice. (C) T cells activated within the liver are committed to reduced half-life within the first 24 hours following activation. Equal numbers of CFSE-labeled Des-TCR LN cells activated for 24 hours in either liver or LNs of Met-Kb mice were adoptively transferred into a second antigen-free, nontransgenic B10.BR recipient, and 30 days later, lymphocytes from liver, LNs, and spleen were purified as described in Methods. Bars indicate the total number of CD8+ CFSE+ Des-TCR+ cells harvested from the 3 compartments. Plots represent means ± SEM for groups of 3 mice.

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

Sign up for email alerts