Early intrahepatic antigen-specific retention of naïve CD8+ T cells is predominantly ICAM-1/LFA-1 dependent in mice

Authors

  • Patrick Bertolino,

    Corresponding author
    1. AW Morrow Gastroenterology and Liver Centre & Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, University of Sydney, Australia
    • AW Morrow Gastroenterology and Liver Centre, Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No 6, Newtown NSW 2042, Australia
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    • fax: (61) 2-9565-6101

  • Arnhild Schrage,

    1. Exp. Rheumatologie, Med. Klinik, Charite Universitätsmedizin Berlin and Dt. Rheumaforschungszentrum, Berlin, Germany
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  • David G. Bowen,

    1. AW Morrow Gastroenterology and Liver Centre & Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, University of Sydney, Australia
    Current affiliation:
    1. Center for Vaccines and Immunity, Columbus Children's Research Institute, Columbus, OH
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  • Katja Klugewitz,

    1. Exp. Rheumatologie, Med. Klinik, Charite Universitätsmedizin Berlin and Dt. Rheumaforschungszentrum, Berlin, Germany
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  • Saeed Ghani,

    1. Exp. Rheumatologie, Med. Klinik, Charite Universitätsmedizin Berlin and Dt. Rheumaforschungszentrum, Berlin, Germany
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  • Katharina Eulenburg,

    1. Exp. Rheumatologie, Med. Klinik, Charite Universitätsmedizin Berlin and Dt. Rheumaforschungszentrum, Berlin, Germany
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  • Lauren Holz,

    1. AW Morrow Gastroenterology and Liver Centre & Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, University of Sydney, Australia
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  • Nancy Hogg,

    1. Leukocyte Adhesion Laboratory, Cancer Research UK London Research Institute, London, UK
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  • Geoffrey W. McCaughan,

    1. AW Morrow Gastroenterology and Liver Centre & Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, University of Sydney, Australia
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  • Alf Hamann

    Corresponding author
    1. Exp. Rheumatologie, Med. Klinik, Charite Universitätsmedizin Berlin and Dt. Rheumaforschungszentrum, Berlin, Germany
    • AW Morrow Gastroenterology and Liver Centre, Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No 6, Newtown NSW 2042, Australia
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  • Potential conflict of interest: Nothing to report.

Abstract

We have previously shown that naïve CD8+ T cells recognizing their cognate antigen within the liver are retained and undergo activation in situ, independent from lymphoid tissues. Intrahepatic primary T cell activation results in apoptosis and may play a crucial role in the ability of the liver to induce tolerance. Although adhesion molecules required for intrahepatic retention of T cells that have undergone previous extra-hepatic activation have been characterized, adhesive interactions involved in selective antigen-dependent intrahepatic retention of naïve CD8+ T cells have not been investigated. By adoptively transferring radiolabeled T cell receptor (TCR)-transgenic CD8+ T cells into recipient animals ubiquitously expressing the relevant antigen, we show that 40% to 60 % of donor antigen–specific naïve CD8+ T cells were retained in the liver within 1 hour after transfer, despite ubiquitous expression of the antigen. Intravital microscopy showed that most donor naïve T cells slowed down and were irreversibly retained intrahepatically within the first few minutes after adoptive transfer, strongly suggesting that they were directly activated by liver cells in situ. This process was largely dependent on LFA-1 and ICAM-1, but was independent of blocking with antibodies against VCAM-1, α4 integrin, P-selectin, VAP-1, and β1 integrin. ICAM-2 seemed to play only a minor role in this process. Interestingly, LFA-1 expressed by both donor T cells and liver cells was involved in retention of the antigen-reactive T cells. In conclusion, LFA-1–dependent intrahepatic T cell retention and activation are linked events that may play a crucial role in the establishment of liver-induced antigen-specific tolerance. Supplementary material for this article can be found on the HEPATOLOGYwebsite (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2005;42:1063–1071.)

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