title: Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.
abstract: A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood-derived T cells, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets. Our knowledge of the insulitic T cell repertoire is derived from histological and immunohistochemical analyses of insulitis, the identification of autoreactive CD8+T cells in situ, in islets of human leukocyte antigen (HLA)-A2+donors and isolation and identification of DQ8 and DQ2-DQ8 heterodimer-restricted, proinsulin-reactive CD4+T cells grown from islets of a single donor with T1D. Here we present an analysis of 50 of a total of 236 CD4+and CD8+T cell lines grown from individual handpicked islets or clones directly sorted from handpicked, dispersed islets from nine donors with T1D. Seventeen of these T cell lines and clones reacted to a broad range of studied native islet antigens and to post-translationally modified peptides. These studies demonstrate the existence of a variety of islet-infiltrating, islet-autoantigen reactive T cells in individuals with T1D, and these data have implications for the design of successful immunotherapies.
authors: Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Jenny Aurielle B
authors: 0000-0001-8843-1179
authors: JA
authors: Babon
authors: Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Megan E
authors: ME
authors: DeNicola
authors: Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: David M
authors: DM
authors: Blodgett
authors: Laboratory for Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors: Inne
authors: I
authors: Crèvecoeur
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Thomas S
authors: TS
authors: Buttrick
authors: Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: René
authors: R
authors: Maehr
authors: Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, Pennsylvania, USA.|Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
authors: Rita
authors: R
authors: Bottino
authors: Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Ali
authors: A
authors: Naji
authors: Department of Information Sciences, Beckman Research Institute, City of Hope, Duarte, California, USA.
authors: John
authors: J
authors: Kaddis
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Wassim
authors: W
authors: Elyaman
authors: Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
authors: Eddie A
authors: EA
authors: James
authors: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors: Rachana
authors: R
authors: Haliyur
authors: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors: Marcela
authors: M
authors: Brissova
authors: Laboratory for Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors: Lut
authors: L
authors: Overbergh
authors: Laboratory for Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors: Chantal
authors: C
authors: Mathieu
authors: Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
authors: Thomas
authors: T
authors: Delong
authors: Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
authors: Kathryn
authors: K
authors: Haskins
authors: Diabetes Research Institute, University of Miami, Miami, Florida, USA.
authors: Alberto
authors: A
authors: Pugliese
authors: Departments of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, USA.
authors: Martha
authors: M
authors: Campbell-Thompson
authors: Departments of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, USA.
authors: Clayton
authors: C
authors: Mathews
authors: Departments of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, USA.
authors: Mark A
authors: MA
authors: Atkinson
authors: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
authors: Alvin C
authors: AC
authors: Powers
authors: Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: David M
authors: DM
authors: Harlan
authors: Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Sally C
authors: SC
authors: Kent
mesh_terms: D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000276:immunology*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D001324:Autoantigens; D015789:HLA-A2 Antigen; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen