CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets.
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.
Khandoga
Andrej
A
Institute for Surgical Research, Ludwig-Maximilians-University of Munich, Germany. Andrej.Khandoga@med-uni-muenchen.de
Hanschen
Marc
M
Kessler
Julia S
JS
Krombach
Fritz
F
D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D005802:Genes, MHC Class II / Q000276:immunology / Q000502:physiology; D008099:Liver / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D020556:Neutrophil Infiltration / Q000502:physiology; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*