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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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Categories: 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 1

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Early activation of naive CD8+ Des-TCR T cells occurred independently wi...
Early activation of naive CD8+ Des-TCR T cells occurred independently within the liver and LNs of Met-Kb mice. CFSE-labeled Des-TCR LN cells were adoptively transferred into Met-Kb and control B10.BR mice, and organs were harvested 2 hours 15 minutes later. Lymphocytes isolated from blood, liver, spleen, and LNs were analyzed by flow cytometry. Representative histograms show CD69 expression by CFSE+ CD8+ CD44low cells within a forward and side scatter gate appropriate for lymphocytes.
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