To understand the role of HSC in liver immunity, we investigated the effect of this transition on T cell stimulation in vitro. Unlike quiescent HSC, activated HSC did not induce proliferation of antigen-specific T cells. Phenotypic analysis of quiescent and activated HSC revealed that activated HSC expressed

the coinhibitory molecule B7-H4. Silencing B7-H4 by small interfering RNA (siRNA) in activated HSC restored the ability of T cells to proliferate, differentiate, and regain effector recall responses. Furthermore, expression of B7-H4 on HSC inhibits early T cell activation and addition of exogenous interleukin (IL)-2 reversed the T cell anergy induced by activated HSC. Conclusion: These studies reveal a novel role for activated

HSC GPCR & G Protein inhibitor in the attenuation of intrahepatic T cell responses by way of expression of the coinhibitory molecule B7-H4, and may provide fundamental insight into intrahepatic immunity during liver fibrogenesis. (HEPATOLOGY 2010) Chronic liver disease is the tenth leading cause of mortality in the United States.1 Whether a viral infection such as hepatitis C virus (HCV) or a noninfectious insult such as alcohol or a genetic disease is the inciting agent, each shares a common route to eventual liver failure characterized by inflammation, fibrosis, and cirrhosis.2 Hepatic stellate cells (HSC) are the major cell types in the liver responsible for liver fibrosis.3 These cells are nonparenchymal cells that comprise 5%-8% of the normal liver, located in the space of Disse between the endothelial layer and parenchymal hepatocytes,4 and serve as a depot of vitamin see more A.5 In the healthy liver, HSC are present in a quiescent form and perform multiple physiologic functions including directing hepatic development and regeneration as well as producing lipoproteins, growth factors, and cytokines.5 However, during liver injury HSC become activated,6

leading to a phenotypic and functionally consequent transformation. Activated HSC (AHSC) are the major mediators MCE of liver fibrosis through extracellular matrix deposition (type I and type III collagen), secretion of the vasoconstrictor endothelin-1 which contributes to portal hypertension, and reduced production of matrix metalloprotease-1 necessary for the degradation of collagen type 1.5 In addition to their role in liver fibrosis, recent evidence has also placed HSC at the center of the intrahepatic immune response.7 HSC secrete chemokines, express various Toll-like receptors, and are phagocytic.7 HSC have been shown to prevent graft rejection in a transplantation model by inhibiting T cell responses8 and have also been shown to expand regulatory T cells in an interleukin (IL)-2-dependent manner.9 AHSC interact with, and in fact, also engulf lymphocytes through phagocytosis during liver fibrosis.