한빛사논문
Abstract
Keunok Jung1, Miseon Kang2, Cheol Park3, Yung Hyun Choi3, Youkyung Jeon1, Se-Ho Park4, Su-Kil Seo1, Dan Jin5, Inhak Choi1,*
1Department of Microbiology and Immunology, Advanced Research Center for Multiple Myeloma
2Department of Pathology, Inje University College of Medicine, Busan 614-735
3Department of Biochemistry and Research Institute of Oriental Medicine, Dongeui University College of Oriental Medicine, Busan 614-052
4School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea
5Department of Immunology and Pathogenic Biology, College of Medicine, Yanbian University, Yanji, Jilin 133002, China
*Correspondence
Abstract
V-set and Ig domain-containing 4 (VSIG4, CRIg, or Z39Ig), a newly-identified B7-related co-signaling molecule, is a complement receptor and a co-inhibitory 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 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 downregulation of G1 phase-specific Cdk2, Cdk4, and Cdk6, and upregulation of tolerance-inducing p27KIP-1 in VSIG4.Ig-stimulated T-cells. Administration of soluble VSIG4.Ig to WT 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.)
Keywords:VSIG4;Liver;Tolerance;Kupffer cells;autoimmune hepatitis
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