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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.
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Article Immunology

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

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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

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Figure 2

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Administration of anti-CD62L antibody reduced LN entry by CD8+ Des-TCR T...
Administration of anti-CD62L antibody reduced LN entry by CD8+ Des-TCR T cells but did not affect their intrahepatic activation or proliferation in Met-Kb mice. (A) Total number of Ly5.1– CD8+ Des-TCR T cells in various organs of Ly5.1+ Met-Kb mice pretreated with anti-CD62L mAb or PBS and injected 4 hours later with Ly5.1– Des-TCR LN cells. Organs were harvested 4 hours after cell transfer. (B) CD69 expression by donor Ly5.1– CD8+ Des-TCR T cells (solid line) versus recipient Ly5.1+ CD8+ T cells (dotted line) within the livers of Met-Kb mice at 4 hours after adoptive transfer. Representative histograms were gated on forward and side scatter gates appropriate for lymphocytes, and Ly5.1– CD8+ PI– cells for CD8+ Des-TCR T cells or Ly5.1+ CD8+ PI– cells for liver resident non–Des-TCR CD8+ T cells. (C) CFSE profiles of donor CD8+ Des-TCR T lymphocytes, at 2.5 days after transfer, isolated from non-splenectomized and splenectomized Met-Kb (shaded plot) and B10.BR (dashed line) mice preadministered control purified rat IgG, or Met-Kb mice preadministered anti-CD62L mAb (solid line). CD8+ Des-TCR T cells did not proliferate in the livers of B10.BR mice administered anti-CD62L (data not shown). (D) CFSE profiles of donor CD8+ Des-TCR lymphocytes isolated from the liver (solid line) and LNs (shaded plot) of Met-Kb mice administered control rat IgG illustrate that donor T cells activated at these 2 sites proliferated at a similar rate.

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

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