In situ targeting of dendritic cells sets tolerogenic environment and ameliorates CD4+ T cell response in the postischemic liver

Background:

CD4+T cells recruited to the liver play a key role in the pathogenesis of ischemia/reperfusion (I/R) injury. The mechanism of their activation during alloantigen-independent I/R remains unclear. We hypothesized that liver-resident dendritic cells (DCs) interact with CD4+T cells in the postischemic liver and modulation of DCs or T cell-DC-interactions attenuates liver inflammation.

Methods:

In mice, warm hepatic I/R was induced. Tolerogenic DCs were generated in situ by pretreatment of animals with the Vitamin D analogue paricalcitol. Anti-CD44 antibody was used for blockade of CD4+T cell-DC interactions.

Results:

As shown by two photon in vivo microscopy as well as confocal microscopy, CD4+T cells were closely colocalized with DCs in the postischemic liver. Pretreatment with paricalcitol attenuated I/R-induced maturation of DCs (flow cytometry), CD4+T cell recruitment into the liver (intravital microscopy), and hepatocellular/microvascular damage (intravital microscopy, ALT/AST, histology). However, interruption of T cell-DC interaction increased proinflammatory DC maturation and even enhanced tissue damage. Simultaneous treatment with an anti-CD44mAb completely abolished the beneficial effect of paricalcitol on T cell migration and tissue injury.

Conclusion:

Our study demonstrates for the first time that i) hepatic DCs interact with CD4+T cells in the postischemic liver in vivo; ii) modulation of DCs and/or generation of tolerogenic DCs attenuates intrahepatic CD4+T cell recruitment and reduces I/R injury; iii) interruption of CD44-dependent CD4+T cell-DC interactions, however, enhances tissue injury probably by affecting „protective” T cell subpopulations and increasing the amount of proinflammatory DCs.