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

Abstract

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 is not completely understood. We hypothesized that liver-resident dendritic cells (DCs) interact with CD4 T cells in the postischemic liver and that modulation of DCs or T-cell-DC interactions attenuates liver inflammation. In mice, warm hepatic I/R (90/120-240 min) was induced. Tolerogenic DCs were generated by pretreatment of animals with the vitamin D analog paricalcitol. A mAb-CD44 was used for blockade of CD4 T-cell-DC interactions. As shown by 2-photon 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, alanine aminotransferase/aspartate aminotransferase, 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. Our study demonstrates for the first time that hepatic DCs interact with CD4 T cells in the postischemic liver ; modulation of DCs and/or generation of tolerogenic DCs attenuates intrahepatic CD4 T-cell recruitment and reduces I/R injury; and interruption of CD44-dependent CD4 T-cell-DC interactions enhances tissue injury by preventing the modulatory effect of hepatic DCs on T cells, especially type 1 T helper effector cells. Thus, hepatic DCs are strongly involved in the promotion of CD4 T-cell-dependent postischemic liver inflammation.-Funken, D., Ishikawa-Ankerhold, H., Uhl, B., Lerchenberger, M., Rentsch, M., Mayr, D., Massberg, S., Werner, J., Khandoga, A. targeting of dendritic cells sets tolerogenic environment and ameliorates CD4 T-cell response in the postischemic liver.

Hepatic Dendritic Cells, the Tolerogenic Liver Environment, and Liver Disease

“…For example, CD4 þ T cell and DC interaction in the post-ischemic liver attenuates further CD4 þ T cells recruitment and reduces IR injury. 59,60 Multiple mechanisms that may contribute to regulation of the inflammatory response in liver IR by HDCs are depicted in (►Fig. 2).…”

The role of dendritic cells regulated by HMGB1/TLR4 signalling pathway in myocardial ischaemia reperfusion injury

“…This is due to its role in regulating immune function, which is closely related to the maturation, activation degree, quantity and local microenvironment of DCs. [8][9][10] In addition, little is known about its function, occurrence, and interaction between groups. A considerable amount of literature has been published about liver and kidney IRI, however, no previous study has investigated that which signalling pathway mediates DCs in the MI/RI process, so the role of DCs in the pathogenesis of MI/RI needs more researches to explore.…”

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection

“…More recent work (49) indicates that signaling via the prostaglandin E receptor EP3 in DCs promotes liver repair after warm IR by inducing IL-13-mediated switching of macrophages from pro-inflammatory to IL-10-producing, reparative cells. Vitamin D analogue administration promotes regulatory DCs and attenuates liver warm IRI, whereas interruption of DC-T cell interaction enhances proinflammatory DC maturation and tissue damage (47). Adoptive transfer of wild-type (WT) but not DAP12-/-cDCs reduces warm liver IRI in DAP12-/-mice that exhibit enhanced tissue injury compared with WT animals (48).…”