title: High-throughput T-cell receptor sequencing across chronic liver diseases reveals distinct disease-associated repertoires.
abstract: Hepatic T-cell infiltrates and a strong genetic human leukocyte antigen association represent characteristic features of various immune-mediated liver diseases. Conceptually the presence of disease-associated antigens is predicted to be reflected in T-cell receptor (TCR) repertoires. Here, we aimed to determine if disease-associated TCRs could be identified in the nonviral chronic liver diseases primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and alcoholic liver disease (ALD). We performed high-throughput sequencing of the TCRβ chain complementarity-determining region 3 of liver-infiltrating T cells from PSC (n = 20), PBC (n = 10), and ALD (n = 10) patients, alongside genomic human leukocyte antigen typing. The frequency of TCRβ nucleotide sequences was significantly higher in PSC samples (2.53 ± 0.80, mean ± standard error of the mean) compared to PBC samples (1.13 ± 0.17, P < 0.0001) and ALD samples (0.62 ± 0.10, P < 0.0001). An average clonotype overlap of 0.85% was detected among PSC samples, significantly higher compared to the average overlap of 0.77% seen within the PBC (P = 0.024) and ALD groups (0.40%, P < 0.0001). From eight to 42 clonotypes were uniquely detected in each of the three disease groups (≥30% of the respective patient samples). Multiple, unique sequences using different variable family genes encoded the same amino acid clonotypes, providing additional support for antigen-driven selection. In PSC and PBC, disease-associated clonotypes were detected among patients with human leukocyte antigen susceptibility alleles.
  
  
  CONCLUSIONS
  We demonstrate liver-infiltrating disease-associated clonotypes in all three diseases evaluated, and evidence for antigen-driven clonal expansions. Our findings indicate that differential TCR signatures, as determined by high-throughput sequencing, may represent an imprint of distinctive antigenic repertoires present in the different chronic liver diseases; this thereby opens up the prospect of studying disease-relevant T cells in order to better understand and treat liver disease.
authors.affiliation: Centre for Liver Research, National Institute for Health Research Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
authors.forename: Evaggelia
authors.initials: E
authors.lastname: Liaskou
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Eva Kristine
authors.initials: EK
authors.lastname: Klemsdal Henriksen
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Holm
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Kaveh
authors.affiliation: Adaptive Biotechnologies Corp., Seattle, WA.
authors.forename: David
authors.initials: D
authors.lastname: Hamm
authors.affiliation: Centre for Liver Research, National Institute for Health Research Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
authors.forename: Janine
authors.initials: J
authors.lastname: Fear
authors.affiliation: Institute of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Marte K
authors.initials: MK
authors.lastname: Viken
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery, 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 Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Johannes Roksund
authors.initials: JR
authors.lastname: Hov
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Harlan
authors.initials: H
authors.lastname: Robins
authors.affiliation: K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of 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 Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery, 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 Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Centre for Liver Research, National Institute for Health Research Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
mesh_terms: D000328:Adult; D015209:Cholangitis, Sclerosing / Q000276:immunology*; D002908:Chronic Disease; D005260:Female; D019674:Genes, T-Cell Receptor beta; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D008108:Liver Diseases, Alcoholic / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta