title: β-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure.
abstract: Autoreactive CD8 T cells play a central role in the destruction of pancreatic islet β-cells that leads to type 1 diabetes, yet the key features of this immune-mediated process remain poorly defined. In this study, we combined high-definition polychromatic flow cytometry with ultrasensitive peptide-human leukocyte antigen class I tetramer staining to quantify and characterize β-cell-specific CD8 T cell populations in patients with recent-onset type 1 diabetes and healthy control subjects. Remarkably, we found that β-cell-specific CD8 T cell frequencies in peripheral blood were similar between subject groups. In contrast to healthy control subjects, however, patients with newly diagnosed type 1 diabetes displayed hallmarks of antigen-driven expansion uniquely within the β-cell-specific CD8 T cell compartment. Molecular analysis of selected β-cell-specific CD8 T cell populations further revealed highly skewed oligoclonal T cell receptor repertoires comprising exclusively private clonotypes. Collectively, these data identify novel and distinctive features of disease-relevant CD8 T cells that inform the immunopathogenesis of type 1 diabetes.
authors.affiliation: Department of Immunobiology, King's College London School of Medicine, London, UK.
authors.forename: Ania
authors.initials: A
authors.lastname: Skowera
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: McLaren
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Garry
authors.initials: G
authors.lastname: Dolton
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, UK.|QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthews
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.affiliation: Department of Immunobiology, King's College London School of Medicine, London, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kronenberg-Versteeg
authors.affiliation: Department of Immunobiology, King's College London School of Medicine, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Eichmann
authors.affiliation: Department of Immunobiology, King's College London School of Medicine, London, UK.
authors.forename: Robin R
authors.initials: RR
authors.lastname: Knight
authors.affiliation: National Institute for Health Research Biomedical Research Centre at Guy's & St Thomas' National Health Service Foundation Trust and King's College London, London, UK.
authors.forename: Susanne
authors.initials: S
authors.lastname: Heck
authors.affiliation: Department of Diabetes and Endocrinology, Guy's & St Thomas' National Health Service Foundation Trust, London, UK.
authors.forename: Jake
authors.initials: J
authors.lastname: Powrie
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.affiliation: Institute of Molecular & Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dayan
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, UK.|QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.|School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Department of Immunobiology, King's College London School of Medicine, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
mesh_terms: D000328:Adult; D001324:Autoantigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000276:immunology*; D008297:Male; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology
chemical_list: D001324:Autoantigens; C516862:PTPRN protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2