title: CD8+ T Cells That Coexpress RORγt and T-bet Are Functionally Impaired and Expand in Patients with Distal Bile Duct Cancer.
abstract: CD8+T cells that express retinoic acid-related orphan receptor (ROR)γt (TC17 cells) have been shown to promote procarcinogenic inflammation and contribute to a tolerogenic microenvironment in tumors. We investigated their phenotype and functional properties in relationship to the pathogenesis of human distal bile duct cancer (DBDC). DBDC patients had an elevated level of type 17 immune responses and the frequency of CD8+RORγt+T cells (TC17 cells) was increased in peripheral blood. The CD8+RORγt+T cells represented a highly activated subset and produced IL-17A in equal amount as CD4+RORγt+T cells (TH17 cells). Most CD8+RORγt+T cells coexpressed T-bet, a lineage transcription factor for TH1 and TC1 development, suggesting that CD8+RORγt+T cells undergo plasticity toward a TC17/1-like phenotype with coproduction of IL-17A and INF-γ. In comparison with CD8+RORγt-T cells, the CD8+RORγt+T cells had a higher level of TCR signaling and were terminally differentiated and exhausted. These cells also had impaired ability to re-express perforin after degranulation and reduced cytotoxic immune function. A subset of CD8+RORγt+T cells expressing a low level of programmed cell death protein 1 and a high level of OX40 were associated with reduced patient survival. In conclusion, CD8+RORγt+T cells are proinflammatory and functionally impaired and may contribute to the pathogenesis of DBDC.
authors.affiliation: Center for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo and Oslo University Hospital, 0318 Oslo, Norway.|Biotechnology Center, University of Oslo, 0316 Oslo, Norway.|K.G. Jebsen Inflammation Research Center, University of Oslo, 0424 Oslo, Norway.|K.G. Jebsen Center for Cancer Immunotherapy, University of Oslo, 0379 Oslo, Norway.
authors.forename: Stalin
authors.identifier: 0000-0002-6248-2290
authors.initials: S
authors.lastname: Chellappa
authors.affiliation: Section for Transplantation Surgery, Oslo University Hospital, 0424 Oslo, Norway.|Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Harald
authors.identifier: 0000-0002-1114-5366
authors.initials: H
authors.lastname: Hugenschmidt
authors.affiliation: Center for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo and Oslo University Hospital, 0318 Oslo, Norway.|Biotechnology Center, University of Oslo, 0316 Oslo, Norway.|K.G. Jebsen Inflammation Research Center, University of Oslo, 0424 Oslo, Norway.|Section for Transplantation Surgery, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Morten
authors.initials: M
authors.lastname: Hagness
authors.affiliation: Center for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo and Oslo University Hospital, 0318 Oslo, Norway.
authors.forename: Saranya
authors.initials: S
authors.lastname: Subramani
authors.affiliation: K.G. Jebsen Inflammation Research Center, University of Oslo, 0424 Oslo, Norway.|Norwegian Primary Sclerosing Cholangitis Research Center, Research Institute of Internal Medicine, Section of Gastroenterology, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.affiliation: Section for Transplantation Surgery, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Pål Dag
authors.identifier: 0000-0002-5884-9336
authors.initials: PD
authors.lastname: Line
authors.affiliation: Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Knut-Jørgen
authors.initials: KJ
authors.lastname: Labori
authors.affiliation: Department of Gastrointestinal Surgery, Oslo University Hospital, 0317 Oslo, Norway; and.
authors.forename: Gro
authors.initials: G
authors.lastname: Wiedswang
authors.affiliation: Center for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo and Oslo University Hospital, 0318 Oslo, Norway.|Biotechnology Center, University of Oslo, 0316 Oslo, Norway.|K.G. Jebsen Inflammation Research Center, University of Oslo, 0424 Oslo, Norway.|K.G. Jebsen Center for Cancer Immunotherapy, University of Oslo, 0379 Oslo, Norway.|Department of Infectious Diseases, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
authors.affiliation: Center for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo and Oslo University Hospital, 0318 Oslo, Norway; e.m.aandahl@biotek.uio.no.|Biotechnology Center, University of Oslo, 0316 Oslo, Norway.|K.G. Jebsen Inflammation Research Center, University of Oslo, 0424 Oslo, Norway.|Section for Transplantation Surgery, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Einar Martin
authors.initials: EM
authors.lastname: Aandahl
mesh_terms: D000368:Aged; D001650:Bile Duct Neoplasms / Q000276:immunology* / Q000503:physiopathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics* / Q000378:metabolism; D053278:OX40 Ligand; D054353:Perforin / Q000235:genetics; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016019:Survival Analysis; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000235:genetics; D000098815:T-bet Transcription Factor
chemical_list: C508717:IL17A protein, human; D020381:Interleukin-17; D008562:Membrane Glycoproteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D053278:OX40 Ligand; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D054353:Perforin; D007371:Interferon-gamma