Hepatic Stellate Cells Modulate the Phenotype of Liver Myeloid Dendritic Cells Rendering Them Tolerogenic

Abstract

Liver exhibits immune tolerance as illustrated by spontaneous acceptance of the allograft across MHC barriers in rodents and several cases of human transplantation. Since, rejections of the allografts still a major clinical problem, precise understanding of the mechanisms underlying the tolerogenic property of liver is important. Evidence indicates that the perisinusoidal hepatic stellate cells (HSCs) play an important role in hepatic tolerance by interacting with the immune‐regulatory cells. We hypothesized that HSCs might regulate migratory antigen‐presenting dendritic cells (DCs) in determining the fate of liver graft. We observed that myeloid (m) DCs co‐localize in vivo and in vitro with HSCs. Such association increases in transplantation due to ischemia/reperfusion‐induced disruption of endothelial barrier. In co‐culture, HSCs up‐regulated the expression of MHC II, CD80, CD86, and inhibitory ligand B7‐H1 on mDCs. The co‐culture also resulted in increased production of IL‐6 and IL‐10. HSCs suppressed the ability of mDCs to induce proliferation of allogeneic CD4+ and CD8+ T cells. HSC‐induced modulation of mDCs required cell‐cell contact, and was partially dependent on HSC‐derived MIP1á, and IL‐6‐induced STAT3 activation. The results suggest that HSCs play an important role in hepatic immunotolerance by altering the phenotype of mDCs, rendering them tolerogenic. (Supported by NIH PO1A1081678)