Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 40, Pages 16735-16740Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1112251108
Keywords
transgenic mice transplantation; hepatitis C virus; cell-in cell; cannibalism; entosis
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Funding
- National Health and Medical Research Council of Australia [571408]
- Ageing and Alzheimer's Research Foundation
- Deutsche Forschungsgemeinschaft [BE 3256/1-2]
- National Health and Medical Research Council
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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 naive 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 emperipolesis, is a long-observed phenomenon for which a physiological role has not been previously demonstrated. We propose that this suicidal emperipolesis is a unique mechanism of autoreactive T-cell deletion, a process critical for the maintenance of tolerance.
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