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PMID:20209097

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Citation

Mengshol, JA, Golden-Mason, L, Arikawa, T, Smith, M, Niki, T, McWilliams, R, Randall, JA, McMahan, R, Zimmerman, MA, Rangachari, M, Dobrinskikh, E, Busson, P, Polyak, SJ, Hirashima, M and Rosen, HR (2010) A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLoS ONE 5:e9504

Abstract

Approximately 200 million people throughout the world are infected with hepatitis C virus (HCV). One of the most striking features of HCV infection is its high propensity to establish persistence (approximately 70-80%) and progressive liver injury. Galectins are evolutionarily conserved glycan-binding proteins with diverse roles in innate and adaptive immune responses. Here, we demonstrate that galectin-9, the natural ligand for the T cell immunoglobulin domain and mucin domain protein 3 (Tim-3), circulates at very high levels in the serum and its hepatic expression (particularly on Kupffer cells) is significantly increased in patients with chronic HCV as compared to normal controls. Galectin-9 production from monocytes and macrophages is induced by IFN-gamma, which has been shown to be elevated in chronic HCV infection. In turn, galectin-9 induces pro-inflammatory cytokines in liver-derived and peripheral mononuclear cells; galectin-9 also induces anti-inflammatory cytokines from peripheral but not hepatic mononuclear cells. Galectin-9 results in expansion of CD4(+)CD25(+)FoxP3(+)CD127(low) regulatory T cells, contraction of CD4(+) effector T cells, and apoptosis of HCV-specific CTLs. In conclusion, galectin-9 production by Kupffer cells links the innate and adaptive immune response, providing a potential novel immunotherapeutic target in this common viral infection.

Links

PubMed PMC2831996 Online version:10.1371/journal.pone.0009504

Keywords

CD4 Antigens/biosynthesis; CD4-Positive T-Lymphocytes/metabolism; CD4-Positive T-Lymphocytes/virology; Forkhead Transcription Factors/biosynthesis; Galectins/metabolism; Gene Expression Regulation, Viral; Hepacivirus/metabolism; Hepatitis C/metabolism; Humans; Immunotherapy/methods; Interferon-gamma/metabolism; Interleukin-2 Receptor alpha Subunit/biosynthesis; Interleukin-7 Receptor alpha Subunit/biosynthesis; Kupffer Cells/metabolism; Leukocytes, Mononuclear/cytology; Ligands; Macrophages/metabolism; Monocytes/metabolism; T-Lymphocytes/immunology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:LEG9

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(UBERON:0001969)

Seeded From UniProt

complete

HUMAN:LEG9

involved_in

GO:0032834: positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation involved in immune response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LEG9

involved_in

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:2000001)|occurs_in:(CL:0000842)
  • part_of:(UBERON:0002107)

Seeded From UniProt

complete

HUMAN:LEG9

involved_in

GO:0032753: positive regulation of interleukin-4 production

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:2000001)

Seeded From UniProt

complete

HUMAN:LEG9

involved_in

GO:0032736: positive regulation of interleukin-13 production

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:2000001)

Seeded From UniProt

complete

HUMAN:LEG9

involved_in

GO:0032733: positive regulation of interleukin-10 production

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:2000001)

Seeded From UniProt

complete

HUMAN:LEG9

involved_in

GO:0032731: positive regulation of interleukin-1 beta production

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:2000001)

Seeded From UniProt

complete

HUMAN:LEG9

involved_in

GO:0032729: positive regulation of interferon-gamma production

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:2000001)|occurs_in:(CL:0000842)
  • part_of:(UBERON:0002107)

Seeded From UniProt

complete

HUMAN:LEG9

involved_in

GO:2000562: negative regulation of CD4-positive, alpha-beta T cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LEG9

involved_in

GO:0071636: positive regulation of transforming growth factor beta production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LEG9

involved_in

GO:0070241: positive regulation of activated T cell autonomous cell death

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0001049)

Seeded From UniProt

complete

HUMAN:IFNG

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:O00182)
  • occurs_in:(CL:2000001)

Seeded From UniProt

complete

HUMAN:IFNG

involved_in

GO:0032834: positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation involved in immune response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IFNG

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:O00182)
  • occurs_in:(CL:2000001)

Seeded From UniProt

complete

Notes

See also

References

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