Journal article
Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis
M Welz, S Eickhoff, Z Abdullah, J Trebicka, KH Gartlan, JA Spicer, AJ Demetris, H Akhlaghi, M Anton, K Manske, D Zehn, B Nieswandt, C Kurts, JA Trapani, P Knolle, D Wohlleber, W Kastenmüller
Nature Communications | NATURE PUBLISHING GROUP | Published : 2018
Open access
Abstract
CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impair..
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Awarded by Horizon 2020 Framework Programme
Funding Acknowledgements
We would like to thank C. Boerner, S. Ebbinghaus, S. Rathmann, and K. Dumler for technical assistance. This research was supported by the german research foundation DFG (SFB 704, SFB 670, and TRR 179). W.K., Z.A., and C. K. are members of the DFG Excellence Cluster ImmunoSensation in Bonn, Germany. W.K. is supported by NRW-Ruckkehrerprogramm of the German state of Northrhine-Westfalia. D.W. was supported from BONFOR. J.T. was supported by DFG (SFB TRR57 P18), European Union's Horizon 2020 research, the innovation programme (No. 668031), and the Cellex Foundation. P.K. was supported by the German Center for Infection Research, Munich Site.