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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
Author(s) -
Jung Keunok,
Kang Miseon,
Park Cheol,
Hyun Choi Yung,
Jeon Youkyung,
Park SeHo,
Seo SuKil,
Jin Dan,
Choi Inhak
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25906
Subject(s) - biology , natural killer t cell , immune system , immune tolerance , immunology , adoptive cell transfer , t cell , microbiology and biotechnology , cancer research
Abstract 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 G 0 /G 1 phase but did not induce apoptosis in vitro . VSIG4‐mediated tolerance induction and cell‐cycle arrest were further supported by down‐regulation of G 1 phase‐specific Cdk2, Cdk4, and Cdk6, and up‐regulation of tolerance‐inducing p27 KIP‐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. (H EPATOLOGY 2012;56:1838–1848)