title: Detailed analysis of intrahepatic CD8 T cells in the normal and hepatitis C-infected liver reveals differences in specific populations of memory cells with distinct homing phenotypes.
abstract: In hepatitis C virus (HCV) infection the immune response is ineffective, leading to chronic hepatitis and liver damage. Primed CD8 T cells are critical for antiviral immunity and subsets of circulating CD8 T cells have been defined in blood but these do not necessarily reflect the clonality or differentiation of cells within tissue. Current models divide primed CD8 T cells into effector and memory cells, further subdivided into central memory (CCR7+, L-selectin+), recirculating through lymphoid tissues and effector memory (CCR7-, L-selectin-) mediating immune response in peripheral organs. We characterized CD8 T cells derived from organ donors and patients with end-stage HCV infection to show that: 1) all liver-infiltrating CD8 T cells express high levels of CD11a, indicating the effective absence of naive CD8 T cells in the liver. 2) The liver contains distinct subsets of primed CD8+ T cells including a population of CCR7+ L-selectin- cells, which does not reflect current paradigms. The expression of CCR7 by these cells may be induced by the hepatic microenvironment to facilitate recirculation. 3) The CCR7 ligands CCL19 and CCL21 are present on lymphatic, vascular, and sinusoidal endothelium in normal liver and in patients with HCV infection. We suggest that the recirculation of CCR7+/L-selectin- intrahepatic CD8 T cells to regional lymphoid tissue will be facilitated by CCL19 and CCL21 on hepatic sinusoids and lymphatics. This centripetal pathway of migration would allow restimulation in lymph nodes, thereby promoting immune surveillance in normal liver and renewal of effector responses in chronic viral infection.
authors.affiliation: Liver Research Laboratories, Medical Research Council, Centre for Immune Regulation, University of Birmingham, Birmingham, UK. m.heydtmann@bham.ac.uk
authors.forename: Mathis
authors.initials: M
authors.lastname: Heydtmann
authors.forename: Debbie
authors.initials: D
authors.lastname: Hardie
authors.forename: Philip L
authors.initials: PL
authors.lastname: Shields
authors.forename: Jeff
authors.initials: J
authors.lastname: Faint
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.forename: James J
authors.initials: JJ
authors.lastname: Campbell
authors.forename: Michael
authors.initials: M
authors.lastname: Salmon
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D040881:CD11a Antigen / Q000096:biosynthesis / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000276:immunology*; D054415:Chemokine CCL19; D019742:Chemokines, CC / Q000097:blood / Q000378:metabolism; D002648:Child; D016174:Hepacivirus / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000096:biosynthesis / Q000097:blood; D008024:Ligands; D008103:Liver Cirrhosis / Q000276:immunology / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis / Q000097:blood; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D019707:Receptors, Chemokine / Q000097:blood / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis* / Q000097:blood; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis / Q000097:blood
chemical_list: C515460:CCL19 protein, human; C515370:CCR7 protein, human; D040881:CD11a Antigen; D054415:Chemokine CCL19; D019742:Chemokines, CC; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D016201:Receptors, Lymphocyte Homing; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D017493:Leukocyte Common Antigens