Hepatocyte entry leads to degradation of autoreactive CD8 T cells

V Benseler; A Warren; M Vo; LE Holz; SS Tay; DG Le Couteur; E Breen; AC Allison; N Van Rooijen; C McGuffog; HJ Schlitt; DG Bowen; GW McCaughan; P Bertolino

Journal article

Hepatocyte entry leads to degradation of autoreactive CD8 T cells

V Benseler, A Warren, M Vo, LE Holz, SS Tay, DG Le Couteur, E Breen, AC Allison, N Van Rooijen, C McGuffog, HJ Schlitt, DG Bowen, GW McCaughan, P Bertolino

Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2011

DOI: 10.1073/pnas.1112251108

Abstract

Although most self-reactive T cells are eliminated in the thymus, mechanisms to inactivate or control T cells specific for extrathymic antigens are required and exist in the periphery. By investigating the site in which autoreactive T cells are tolerized, we identify a unique mechanism of peripheral deletion in which naïve autoreactive CD8 T cells are rapidly eliminated in the liver after intrahepatic activation. T cells actively invade hepatocytes, enter endosomal/lysosomal compartments, and are degraded. Blockade of this process leads to accumulation of autoreactive CD8 T cells in the liver and breach of tolerance, with the development of autoimmune hepatitis. Cell into cell invasion, or e..

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University of Melbourne Researchers

Lauren Holz Author

Grants

Awarded by National Health and Medical Research Council of Australia

Awarded by Deutsche Forschungsgemeinschaft

Funding Acknowledgements

We thank the Centenary Institute animal and flow cytometry facilities for their technical support; D. Lovejoy for help in performing the radiolabeling experiments; B. Roediger, R. Whan, and E. Kable for help in confocal imaging; A. Strasser, P. Bouillet, and L. O'Reilly for the Bim<SUP>-/-</SUP> mice and the anti-Bim antibody; M. Vadas and W. Weninger for helpful comments on the manuscript; and A. Demetris for reminding us of the literature on emperipolesis. This work was supported by the National Health and Medical Research Council of Australia (Program Grant 571408) and the Ageing and Alzheimer's Research Foundation. V. B. was supported by a Deutsche Forschungsgemeinschaft Postgraduate Research Scholarship (BE 3256/1-2). P. B. was supported by a National Health and Medical Research Council Senior Research Fellowship.