title: Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells.
abstract: Infection with hepatitis B virus (HBV) results in disparate degrees of tissue injury: the virus can either replicate without pathological consequences or trigger immune-mediated necroinflammatory liver damage. We investigated the potential for myeloid-derived suppressor cells (MDSCs) to suppress T cell-mediated immunopathology in this setting. Granulocytic MDSCs (gMDSCs) expanded transiently in acute resolving HBV, decreasing in frequency prior to peak hepatic injury. In persistent infection, arginase-expressing gMDSCs (and circulating arginase) increased most in disease phases characterized by HBV replication without immunopathology, whilst L-arginine decreased. gMDSCs expressed liver-homing chemokine receptors and accumulated in the liver, their expansion supported by hepatic stellate cells. We provide in vitro and ex vivo evidence that gMDSCs potently inhibited T cells in a partially arginase-dependent manner. L-arginine-deprived T cells upregulated system L amino acid transporters to increase uptake of essential nutrients and attempt metabolic reprogramming. These data demonstrate the capacity of expanded arginase-expressing gMDSCs to regulate liver immunopathology in HBV infection.
authors.affiliation: Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Pallett
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Bart's and the London School of Medicine and Dentistry, London, UK.
authors.forename: Upkar S
authors.initials: US
authors.lastname: Gill
authors.affiliation: Institute of Liver Studies, Kings College Hospital, London, UK.
authors.forename: Alberto
authors.initials: A
authors.lastname: Quaglia
authors.affiliation: Division of Cell Signaling and Immunology, University of Dundee, Dundee, UK.
authors.forename: Linda V
authors.initials: LV
authors.lastname: Sinclair
authors.affiliation: Institute of Liver and Digestive Health, University College London, London, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Jover-Cobos
authors.affiliation: Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Schurich
authors.affiliation: Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
authors.forename: Kasha P
authors.identifier: 0000000251999331
authors.initials: KP
authors.lastname: Singh
authors.affiliation: Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
authors.forename: Niclas
authors.initials: N
authors.lastname: Thomas
authors.affiliation: Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Das
authors.affiliation: Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
authors.forename: Antony
authors.initials: A
authors.lastname: Chen
authors.affiliation: Institute of Liver and Digestive Health, University College London, London, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fusai
authors.affiliation: 1] Duke-Nus Medical School, Emerging Infectious Disease Program, Singapore. [2] Singapore Institute for Clinical Sciences, Agency of Science and Technology, Singapore.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
authors.affiliation: Division of Cell Signaling and Immunology, University of Dundee, Dundee, UK.
authors.forename: Doreen A
authors.initials: DA
authors.lastname: Cantrell
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Bart's and the London School of Medicine and Dentistry, London, UK.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Kennedy
authors.affiliation: Institute of Liver and Digestive Health, University College London, London, UK.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Davies
authors.affiliation: 1] Singapore Institute for Clinical Sciences, Agency of Science and Technology, Singapore. [2] Institute of Cellular Medicine, Newcastle University, UK.
authors.forename: Muzlifah
authors.initials: M
authors.lastname: Haniffa
authors.affiliation: Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
mesh_terms: D000293:Adolescent; D000328:Adult; D017951:Antigen Presentation / Q000276:immunology; D001119:Arginase / Q000276:immunology / Q000378:metabolism; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006509:Hepatitis B / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006515:Hepatitis B virus / Q000472:pathogenicity; D006801:Humans; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D039481:CD11b Antigen; D001119:Arginase