title: Gut and liver T-cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease.
abstract: Recruitment of gut-derived memory T-cells to the liver is believed to drive hepatic inflammation in primary sclerosing cholangitis (PSC). However, whether gut-infiltrating and liver-infiltrating T-cells share T cell receptors (TCRs) and antigenic specificities is unknown. We used paired gut and liver samples from PSC patients with concurrent inflammatory bowel disease (PSC-IBD), and normal tissue samples from colon cancer controls, to assess potential T cell clonotype overlap between the two compartments.
  
  
  
  High-throughput sequencing of TCRβ repertoires was applied on matched colon, liver and blood samples from patients with PSC-IBD (n=10), and on paired tumor-adjacent normal gut and liver tissue samples from colon cancer patients (n=10).
  
  
  
  An average of 9.7% (range: 4.7-19.9%) memory T cell clonotypes overlapped in paired PSC-IBD affected gut and liver samples, after excluding clonotypes present at similar frequencies in blood. Shared clonotypes constituted on average 16.0% (range: 8.7-32.6%) and 15.0% (range: 5.9-26.3%) of the liver and gut memory T-cells, respectively. A significantly higher overlap was observed between paired PSC-IBD affected samples (8.7%, p=0.0007) compared to paired normal gut and liver samples (3.6%), after downsampling to equal number of reads.
  
  
  
  Memory T-cells of common clonal origin were detected in paired gut and liver samples of patients with PSC-IBD. Our data indicate that this is related to PSC-IBD pathogenesis, suggesting that memory T-cells driven by shared antigens are present in the gut and liver of PSC-IBD patients. Our findings support efforts to therapeutically target memory T cell recruitment in PSC-IBD.
  
  
  
  Primary sclerosing cholangitis (PSC) is a devastating liver disease strongly associated with inflammatory bowel disease (IBD). The cause of PSC is unknown, but it has been suggested that the immune reactions in the gut and the liver are connected. Our data demonstrate for the first time that a proportion of the T-cells in the gut and the liver react to similar triggers, and that this proportion is particularly high in patients with PSC and IBD.
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Eva Kristine Klemsdal
authors.initials: EK
authors.lastname: Henriksen
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Kristin Kaasen
authors.initials: KK
authors.lastname: Jørgensen
authors.affiliation: K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo, Norway.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Kaveh
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Holm
authors.affiliation: Adaptive Biotechnologies Corp., Seattle, WA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hamm
authors.affiliation: K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Johanna
authors.initials: J
authors.lastname: Olweus
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Centre for Liver Research and NIHR Birmingham Biomedical Research Unit, Institute of Biomedical Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Chung
authors.affiliation: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Pathology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Tor J
authors.initials: TJ
authors.lastname: Eide
authors.affiliation: Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Immune Regulation, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Knut E A
authors.initials: KE
authors.lastname: Lundin
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Kirsten Muri
authors.initials: KM
authors.lastname: Boberg
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Centre for Liver Research and NIHR Birmingham Biomedical Research Unit, Institute of Biomedical Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: Centre for Liver Research and NIHR Birmingham Biomedical Research Unit, Institute of Biomedical Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK. Electronic address: e.liaskou@bham.ac.uk.
authors.forename: Evaggelia
authors.initials: E
authors.lastname: Liaskou
mesh_terms: D015209:Cholangitis, Sclerosing / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D013223:Statistics as Topic; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
keywords: High-throughput sequencing; Human gut; Human liver; IBD; Inflammatory bowel disease; PSC; Sclerosing cholangitis; T cell receptor; Ulcerative colitis