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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, Monica Zen, Lauren Holz, Thomas Davis, Geoffrey W. McCaughan, Patrick Bertolino
David G. Bowen, Monica Zen, Lauren Holz, Thomas Davis, Geoffrey W. McCaughan, Patrick Bertolino
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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 5

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CD8+ Des-TCR T cells were activated within the liver and proliferated fo...
CD8+ Des-TCR T cells were activated within the liver and proliferated following adoptive transfer into H-2dk recipient Alb-Kb and Met-Kb transgenic mice. (A) Alb-Kb, Met-Kb, and control mice were injected with CFSE-labeled syngeneic Des-TCR (H-2dk) LN cells (top panels) or Des-TCR RAG-1–/– (H-2k) LN cells (bottom panels). Lymphocytes were purified from LNs, liver, spleen, and blood of recipient mice at 2 hours 15 minutes following adoptive transfer and analyzed by flow cytometry. Representative histograms show CD69 expression by CFSE+ CD8+ CD44low cells within a forward and side scatter gate appropriate for lymphocytes. (B and C) Alb-Kb, Met-Kb, and control mice were injected with CFSE-labeled syngeneic Des-TCR (H-2dk) LN cells containing 5 × 106 transgenic CD8+ T cells. Lymphocytes were purified from LNs, liver, spleen, and blood of recipient mice at 2.5 days (B) or 6 days (C) following adoptive transfer and analyzed by flow cytometry. Histograms represent CFSE division profiles of CD8+ Des-TCR+ PI– cells within a forward and side scatter gate appropriate for lymphocytes. (D and E) Total numbers of Des-TCR+ CD8+ cells expressing upregulated levels of CD43 activation–associated glycoform in various compartments of Alb-Kb, Met-Kb, and B10.BR mice. CFSE-labeled LN cells from Des-TCR mice were adoptively transferred into Alb-Kb, Met-Kb, and B10.BR mice. Organs were harvested at day 2.5 (D) or day 6 (E), and lymphocytes were isolated and analyzed by flow cytometry. Cell numbers for blood represent Des-TCR CD8+ T cells/ml; plots represent means ± SEM of groups of 3–4 mice.

Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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