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Liver Biology and Pathobiology
Article first published online: 26 JAN 2006
Copyright © 2006 American Association for the Study of Liver Diseases
Volume 43, Issue 2, pages 306–315, February 2006
How to Cite
Khandoga, A., Hanschen, M., Kessler, J. S. and Krombach, F. (2006), CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets. Hepatology, 43: 306–315. doi: 10.1002/hep.21017
This report includes experimental work performed by M.H. in fulfillment of his doctoral thesis requirements.
Potential conflict of interest: Nothing to report.
- Issue published online: 26 JAN 2006
- Article first published online: 26 JAN 2006
- Manuscript Accepted: 30 OCT 2005
- Manuscript Received: 1 JUL 2005
- Deutsche Forschungsgemeinschaft. Grant Number: FOR440/2
- EU FP6 NoE “MAIN”. Grant Number: LSHG-CT-2003-502935
The mechanisms by which T cells contribute to the hepatic inflammation during antigen-independent ischemia/reperfusion (I/R) are not fully understood. We analyzed the recruitment of T cells in the postischemic hepatic microcirculation in vivo and tested the hypothesis that T cells interact with platelets and activate sinusoidal endothelial cells, resulting in microvascular dysfunction followed by tissue injury. Using intravital videofluorescence microscopy, we show in mice that warm hepatic I/R (90/30-140 min) induces accumulation and transendothelial migration of CD4+, but not CD8+ T cells in sinusoids during early reperfusion. Simultaneous visualization of fluorescence-labeled CD4+ T cells and platelets showed that approximately 30% of all accumulated CD4+ T cells were colocalized with platelets, suggesting an interaction between both cell types. Although interactions of CD4+/CD40L−/− T cells with CD40L−/− platelets in wild-type mice were slightly reduced, they were almost absent if CD4+ T cells and platelets were from CD62P−/− mice. CD4 deficiency as well as CD40-CD40L and CD28-B7 disruption attenuated postischemic platelet adherence in the same manner as platelet inactivation with a glycoprotein IIb/IIIa antagonist and reduced neutrophil transmigration, sinusoidal perfusion failure, and transaminase activities. Treatment with an MHC class II antibody, however, did not affect I/R injury. In conclusion, we describe the type, kinetic, and microvascular localization of T cell recruitment in the postischemic liver. CD4+ T cells interact with platelets in postischemic sinusoids, and this interaction is mediated by platelet CD62P. CD4+ T cells activate endothelium, increase I/R-induced platelet adherence and neutrophil migration via CD40-CD40L and CD28-B7-dependent pathways, and aggravate microvascular/hepatocellular injury. (HEPATOLOGY 2006;43:306–315.)