title: Liver-primed CD8+ T cells suppress antiviral adaptive immunity through galectin-9-independent T-cell immunoglobulin and mucin 3 engagement of high-mobility group box 1 in mice.
abstract: The liver is a tolerogenic environment exploited by persistent infections, such as hepatitis B (HBV) and C (HCV) viruses. In a murine model of intravenous hepatotropic adenovirus infection, liver-primed antiviral CD8(+) T cells fail to produce proinflammatory cytokines and do not display cytolytic activity characteristic of effector CD8(+) T cells generated by infection at an extrahepatic, that is, subcutaneous, site. Importantly, liver-generated CD8(+) T cells also appear to have a T-regulatory (Treg) cell function exemplified by their ability to limit proliferation of antigen-specific T-effector (Teff ) cells in vitro and in vivo via T-cell immunoglobulin and mucin 3 (Tim-3) expressed by the CD8(+) Treg cells. Regulatory activity did not require recognition of the canonical Tim-3 ligand, galectin-9, but was dependent on CD8(+) Treg cell-surface Tim-3 binding to the alarmin, high-mobility group box 1 (HMGB-1).
  
  
  CONCLUSIONS
  Virus-specific Tim-3(+) CD8(+) T cells operating through HMGB-1 recognition in the setting of acute and chronic viral infections of the liver may act to dampen hepatic T-cell responses in the liver microenvironment and, as a consequence, limit immune-mediated tissue injury or promote the establishment of persistent infections.
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Dolina
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Braciale
authors.forename: Young S
authors.initials: YS
authors.lastname: Hahn
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology*; D000256:Adenoviridae / Q000502:physiology; D000257:Adenoviridae Infections / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D049109:Cell Proliferation; D060833:Cellular Microenvironment; D004195:Disease Models, Animal; D037161:Galectins / Q000502:physiology*; D024243:HMGB1 Protein / Q000502:physiology*; D007136:Immunoglobulins / Q000502:physiology; D066298:In Vitro Techniques; D008099:Liver / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D051379:Mice; D008815:Mice, Inbred Strains; D055263:Mucin-3 / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: D037161:Galectins; D024243:HMGB1 Protein; D007136:Immunoglobulins; D055263:Mucin-3; C508186:galectin 9, mouse