title: Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection.
abstract: The inflamed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large influx of non-virus-specific CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specificity, were impaired in their ability to produce interleukin-2 and proliferate upon TCR-dependent stimulation. In contrast, these CD8 T cells had preserved production of the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha. This aberrant functional profile was partially attributable to down-regulation of the proximal T cell receptor signaling molecule CD3zeta, and could be corrected in vitro by transfection of CD3zeta or replenishment of the amino acid arginine required for its expression. We provide evidence for depletion of arginine in the inflamed hepatic microenvironment as a potential mechanism for these defects in global CD8 T cell signaling and function. These data imply that polarized CD8 T cells within the HBV-infected liver may impede proliferative antiviral effector function, while contributing to the proinflammatory cytokine environment.
authors.affiliation: Division of Infection and Immunity, University College London, London W1T 4JF, England, UK.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Das
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoare
authors.forename: Nathan
authors.initials: N
authors.lastname: Davies
authors.forename: A Ross
authors.initials: AR
authors.lastname: Lopes
authors.forename: Claire
authors.initials: C
authors.lastname: Dunn
authors.forename: Patrick T F
authors.initials: PT
authors.lastname: Kennedy
authors.forename: Graeme
authors.initials: G
authors.lastname: Alexander
authors.forename: Helene
authors.initials: H
authors.lastname: Finney
authors.forename: Alistair
authors.initials: A
authors.lastname: Lawson
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Plunkett
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D005260:Female; D015789:HLA-A2 Antigen / Q000378:metabolism; D006515:Hepatitis B virus / Q000378:metabolism*; D019694:Hepatitis B, Chronic / Q000097:blood* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019562:Viral Load
chemical_list: D015789:HLA-A2 Antigen; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma