Autoimmune, Cholestatic and Biliary Disease
Article first published online: 31 OCT 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 5, pages 1838–1848, November 2012
How to Cite
Jung, K., Kang, M., Park, C., Hyun Choi, Y., Jeon, Y., Park, S.-H., Seo, S.-K., Jin, D. and Choi, I. (2012), Protective role of V-set and immunoglobulin domain-containing 4 expressed on kupffer cells during immune-mediated liver injury by inducing tolerance of liver T- and natural killer T-cells. Hepatology, 56: 1838–1848. doi: 10.1002/hep.25906
Potential conflict of interest: Nothing to report.
Supported by the National Research Foundation of Korea (NRF) grant (2010-0017987) and a grant from the National R&D Program for Cancer Control (0920040) funded by the MEST and Ministry for Health, Welfare and Family Affairs of the Korean government, respectively (to I.C.).
- Issue published online: 31 OCT 2012
- Article first published online: 31 OCT 2012
- Accepted manuscript online: 18 JUN 2012 11:57AM EST
- Manuscript Accepted: 30 MAY 2012
- Manuscript Received: 25 JAN 2012
V-set and Ig domain-containing 4 (VSIG4, CRIg, or Z39Ig), a newly identified B7-related cosignaling molecule, is a complement receptor and a coinhibitory ligand that negatively regulates T-cell immunity. Despite its exclusive expression on liver Kupffer cells (KCs) that play key roles in liver tolerance, the physiological role of VSIG4 in liver tolerance remains undefined. Mice lacking VSIG4 had poor survival rates and severe liver pathology in a concanavalin A (ConA)-induced hepatitis (CIH) model, which could be prevented by adoptive transfer of VSIG4+ KCs. The absence of VSIG4 rendered endogenous liver T- and natural killer T (NKT)-cells more responsive to antigen-specific stimulation and impaired tolerance induction in those cells against their cognate antigens. T-cell costimulation with VSIG4.Ig suppressed Th1-, Th2-, and Th17-type cytokine production and arrested the cell cycle at the G0/G1 phase but did not induce apoptosis in vitro. VSIG4-mediated tolerance induction and cell-cycle arrest were further supported by down-regulation of G1 phase-specific Cdk2, Cdk4, and Cdk6, and up-regulation of tolerance-inducing p27KIP-1 in VSIG4.Ig-stimulated T-cells. Administration of soluble VSIG4.Ig to wildtype mice prevented CIH development and prolonged the survival of mice with established CIH. Conclusion: Collectively, our results suggest that VSIG4+ KCs play a critical role in the induction and maintenance of liver T- and NKT-cell tolerance, and that modulation of the VSIG4 pathway using a VSIG4.Ig fusion protein may provide useful immunological therapies against immune-mediated liver injury including autoimmune hepatitis. (HEPATOLOGY 2012;56:1838–1848)