title: CD8+T cells specific for the islet autoantigen IGRP are restricted in their T cell receptor chain usage.
abstract: CD8+T cells directed against beta cell autoantigens are considered relevant for the pathogenesis of type 1 diabetes. Using single cell T cell receptor sequencing of CD8+T cells specific for the IGRP265-273epitope, we examined whether there was expansion of clonotypes and sharing of T cell receptor chains in autoreactive CD8+T cell repertoires. HLA-A*0201 positive type 1 diabetes patients (n = 19) and controls (n = 18) were analysed. TCR α- and β-chain sequences of 418 patient-derived IGRP265-273-multimer+CD8+T cells representing 48 clonotypes were obtained. Expanded populations of IGRP265-273-specific CD8+T cells with dominant clonotypes that had TCR α-chains shared across patients were observed. The SGGSNYKLTF motif corresponding to TRAJ53 was contained in 384 (91.9%) cells, and in 20 (41.7%) patient-derived clonotypes. TRAJ53 together with TRAV29/DV5 was found in 15 (31.3%) clonotypes. Using next generation TCR α-chain sequencing, we found enrichment of one of these TCR α-chains in the memory CD8+T cells of patients as compared to healthy controls. CD8+T cell clones bearing the enriched motifs mediated antigen-specific target cell lysis. We provide the first evidence for restriction of T cell receptor motifs in the alpha chain of human CD8+T cells with specificity to a beta cell antigen.
authors.affiliation: DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.|Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.|German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Yannick F
authors.initials: YF
authors.lastname: Fuchs
authors.affiliation: DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Eugster
authors.affiliation: DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.|Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.|German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Sevina
authors.initials: S
authors.lastname: Dietz
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Sebelefsky
authors.affiliation: DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Kühn
authors.affiliation: DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Wilhelm
authors.affiliation: DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.|Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.|German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Lindner
authors.affiliation: Forschergruppe Diabetes e.V., Neuherberg, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Gavrisan
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.|Forschergruppe Diabetes e.V., Neuherberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Knoop
authors.affiliation: Deep-Sequencing Facility SFB655, Biotechnology Center, Technische Universität Dresden, Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dahl
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.|Forschergruppe Diabetes e.V., Neuherberg, Germany.|Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Anette-G
authors.initials: AG
authors.lastname: Ziegler
authors.affiliation: DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.|Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.|German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.|Forschergruppe Diabetes e.V., Neuherberg, Germany.
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells; D005260:Female; D005952:Glucose-6-Phosphatase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D020539:Sequence Analysis, Protein; D055815:Young Adult
chemical_list: D001324:Autoantigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human