Vo, Michelle and Holz, Lauren E. and Wong, Yik Chun and English, Kieran and Benseler, Volker and McGuffog, Claire and Azuma, Miyuki and McCaughan, Geoffrey W. and Bowen, David G. and Bertolino, Patrick (2016) Effector T cell function rather than survival determines extent and duration of hepatitis in mice. JOURNAL OF HEPATOLOGY, 64 (6). pp. 1327-1338. ISSN 0168-8278, 1600-0641
Full text not available from this repository. (Request a copy)Abstract
Background & Aims: Acute hepatitis is often mediated by cytotoxic T lymphocytes (CTLs); however, the intrinsic parameters that limit CTL-mediated liver injury are not well understood. Methods: To investigate whether acute liver damage is limited by molecules that decrease the lifespan or effector function of CTLs, we used a well-characterized transgenic (Tg) mouse model in which acute liver damage develops upon transfer of T cell receptor (TCR) Tg CD8 T cells. Recipient Tg mice received donor TCR Tg T cells deficient for either the pro-apoptotic molecule Bim, which regulates CTL survival, or suppressor of cytokine signaling-1 (SOCS-1), which controls expression of common gamma chain cytokines; the effects of anti-PD-L1 neutralizing antibodies were also assessed. Results: Use of Bim-deficient donor T cells and/or PD-L1 blockade increased the number of intrahepatic T cells without affecting the degree and kinetic of acute hepatitis. In contrast, SOCS-1-deficient T cells induced a heightened, prolonged acute hepatitis caused by their enhanced cytotoxic function and increased expansion. Although they inflicted more severe acute liver damage, SOCS-1-deficient T cells never precipitated chronic hepatitis and became exhausted. Conclusions: The degree of acute hepatitis is regulated by the function of CD8 T cells, but is not affected by changes in CTL lifespan. Although manipulation of the examined parameters affected acute hepatitis, persistent hepatitis did not ensue, indicating that, in the presence of high intrahepatic antigen load, changes in these factors in isolation were not sufficient to prevent T cell exhaustion and mediate progression to chronic hepatitis. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | C VIRUS-INFECTION; MARROW-DERIVED CELLS; CYTOKINE SIGNALING-1; VIRAL CLEARANCE; ACTIVATION; EXPRESSION; RESPONSES; LIVER; SUPPRESSOR; DEATH; Autoimmunity; Transgenic; Liver; Tolerance |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 25 Mar 2019 13:50 |
| Last Modified: | 25 Mar 2019 13:50 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2897 |
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