T lymphocytes interact with hepatocytes through... : Hepatology (original) (raw)

Liver Biology and Pathobiology: Biology

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

Warren, Alessandra1; Le Couteur, David G.1; Fraser, Robin2; Bowen, David G.3; McCaughan, Geoffrey W.4; Bertolino, Patrick4,*

1_Centre for Education and Research on Ageing (CERA) and the ANZAC Research Institute, Concord RG Hospital and University of Sydney, Sydney, Australia_

2_Department of Pathology, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch, New Zealand_

3_Center for Vaccines and Immunity, Columbus Children's Research Institute, Columbus, Ohio_

4_AW Morrow Gastroenterology and Liver Centre, Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia_

*Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No 6, Newtown 2042, NSW Australia

Email:[email protected]

Received 19 February 2006; Accepted 8 August 2006

Published online in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: National Health and Medical Research Council of Australia (NHMRC); Grant sponsor: Ageing and Alzheimers Research Foundation; Grant sponsor: NHMRC Postgraduate Research Scholarship and an NHMRC CJ Martin Fellowship.

See Editorial on Page 1083

Potential conflict of interest: Nothing to report.

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Abstract

The liver has an established ability to induce tolerance. Recent evidence indicates that this unique property might be related to its distinctive architecture allowing T cells to be activated in situ independently of lymphoid tissues. Unlike lymph node–activated T cells, liver-activated T cells are short-lived, a mechanism that might contribute to the “liver tolerance effect.” Although the potential role of hepatocytes as tolerogenic antigen-presenting cells has been demonstrated, the question as to whether these cells are able to interact with CD8+ T cells in physiological settings remains controversial. Contradicting the immunological dogma stating that naïve T lymphocytes are prevented from interacting with parenchymal cells within non-lymphoid organs by an impenetrable endothelial barrier, we show here that the unique morphology of the liver sinusoidal endothelial cell (LSEC) permits interactions between lymphocytes and hepatocytes. Using electron microscopy, we demonstrate that liver resident lymphocytes as well as circulating naïve CD8+ T cells make direct contact with hepatocytes through cytoplasmic extensions penetrating the endothelial fenestrations that perforate the LSECs. Furthermore, the expression of molecules required for primary T cell activation, MHC class I and ICAM-1, is polarized on hepatocytes to the perisinusoidal cell membrane, thus maximizing the opportunity for interactions with circulating lymphocytes. In conclusion , this study has identified, at the ultrastructural level, a unique type of interaction between naïve T lymphocytes and liver parenchymal cells in vivo . These results hold implications for the pathogenesis of viral hepatitis in which hepatocytes may represent the main antigen-presenting cell, and for the development of immune tolerance as lymphocytes pass through the liver.