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

Keunok Jung, Miseon Kang, Cheol Park, Yung Hyun Choi, Youkyung Jeon, Se-Ho Park, Su Kil Seo, Dan Jin, Inhak Choi

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1838-1848
Number of pages11
JournalHepatology
Volume56
Issue number5
DOIs
Publication statusPublished - 2012 Nov 1

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Natural Killer T-Cells
Kupffer Cells
Liver
Wounds and Injuries
Hepatitis
G1 Phase
T-Lymphocytes
Antigens
Complement Receptors
Autoimmune Hepatitis
Cell Cycle Resting Phase
Adoptive Transfer
Concanavalin A
Cell Cycle Checkpoints
Immunoglobulin Domains
Immunity
Cell Cycle
Up-Regulation
Down-Regulation
Maintenance

ASJC Scopus subject areas

  • Hepatology

Cite this

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. / Jung, Keunok; Kang, Miseon; Park, Cheol; Hyun Choi, Yung; Jeon, Youkyung; Park, Se-Ho; Seo, Su Kil; Jin, Dan; Choi, Inhak.

In: Hepatology, Vol. 56, No. 5, 01.11.2012, p. 1838-1848.

Research output: Contribution to journalArticle

Jung, Keunok ; Kang, Miseon ; Park, Cheol ; Hyun Choi, Yung ; Jeon, Youkyung ; Park, Se-Ho ; Seo, Su Kil ; Jin, Dan ; Choi, Inhak. / 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. In: Hepatology. 2012 ; Vol. 56, No. 5. pp. 1838-1848.
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AU - Park, Cheol

AU - Hyun Choi, Yung

AU - Jeon, Youkyung

AU - Park, Se-Ho

AU - Seo, Su Kil

AU - Jin, Dan

AU - Choi, Inhak

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AB - 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.

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