B7-H4 mediates inhibition of T cell responses by activated murine hepatic stellate cells

• Type of Material: Article
• Authors: Raghavan Chinnadurai, Emory University; Arash Grakoui, Emory University
• Language: English
• Date: 2010-12
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 American Association for the Study of Liver Diseases
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/hep.23953/abstract
• Title of Journal or Parent Work: Hepatology
• ISSN: 0270-9139
• Volume: 52
• Issue: 6
• Start Page: 2177
• End Page: 2185
• Grant/Funding Information: This study was supported in part from the American Liver Foundation Thomas F. Nealon, III Postdoctoral Research Fellowship Honoring Zachery Rue (RC), the Bill and Melinda Gates Foundation Grand Challenges in Global Health (AG, GC#12 to Rafi Ahmed), EVC/CFAR Immunology Core P30 AI050409 (AG), Cancer Research Institute Investigator Award (AG), the Yerkes Research Center Base Grant RR-00165 and the Public Health Service DK083356 and AI070101 (AG).
• Keywords: T cell proliferation; T cell anergy; Stellate cell; B7-family members; liver fibrosis; B7-H4
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Immunology

Abstract

Liver fibrosis is mediated by the transformation of hepatic stellate cells (HSC) from a quiescent to an activated state. 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 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 IL-2 reversed the T cell anergy induced by activated HSC. Conclusions: These studies reveal a novel role for activated HSC in the attenuation of intrahepatic T cell responses via expression of the coinhibitory molecule B7-H4, and may provide fundamental insight into intrahepatic immunity during liver fibrogenesis.