Reciprocal activation between CD4+ T cells and Kupffer cells during hepatic ischemia-reperfusion.
BACKGROUND
Mechanisms mediating CD4+ T-cell recruitment during alloantigen-independent hepatic ischemia-reperfusion (I/R) remain not fully understood. We hypothesized that Kupffer cells activate CD4+ T-cells in the postischemic liver, by the release of free oxygen radicals and cytokines.


METHODS
Recruitment of freshly isolated and fluorescence-labeled CD4+ T-cell was analyzed after hepatic I/R (90/30-120 min) using intravital microscopy in sham-operated mice, in mice after hepatic I/R and in postischemic groups after Kupffer cell depletion, after treatment with antioxidant glutathione, in interleukin (IL)-6-/- mice; and in wild-type mice after infusion of tumor necrosis factor (TNF) receptor-1-/-CD4+ T-cells. Using flow cytometry and immunohistochemistry, we assessed whether Kupffer cell-derived mediators activate CD4+ T-cells and sinusoidal endothelial cells. The clearance kinetics of fluorescence-labeled latex beads was determined as a marker of Kupffer cell activity in vivo.


RESULTS
I/R-induced accumulation of CD4+ T-cells in hepatic sinusoids was significantly attenuated on Kupffer cell depletion, after scavenging of free radicals and after interruption of the IL-6- and TNF-alpha-dependent pathways. These mediators directly activate CD4+ T-cells and up-regulated the expression of T cell-relevant adhesion molecules on sinusoidal endothelial cells. Postischemic activity of Kupffer cells was significantly impaired in wild-type mice, and was even more depressed in CD4-/- animals.


CONCLUSIONS
Kupffer cells trigger recruitment of CD4+ T-cells in the postischemic liver by the release of reactive oxygen species, IL-6, and TNF-alpha. These mediators are capable of activating CD4+ T-cells and sinusoidal endothelial cells. CD4+ T-cells, in turn, influence the activation of Kupffer cells.
Hanschen
Marc
M
Institute for Surgical Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
Zahler
Stefan
S
Krombach
Fritz
F
Khandoga
Andrej
A
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015850:Interleukin-6 / Q000172:deficiency; D007728:Kupffer Cells / Q000166:cytology / Q000276:immunology*; D008102:Liver Circulation / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D015427:Reperfusion Injury / Q000276:immunology*
D015850:Interleukin-6; D047888:Receptors, Tumor Necrosis Factor, Type I