Send to

Choose Destination
Nat Med. 2016 Dec;22(12):1482-1487. doi: 10.1038/nm.4203. Epub 2016 Oct 31.

Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.

Author information

Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Laboratory for Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, Pennsylvania, USA.
Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Information Sciences, Beckman Research Institute, City of Hope, Duarte, California, USA.
Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
Diabetes Research Institute, University of Miami, Miami, Florida, USA.
Departments of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.
Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA.


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.

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing financial interests.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center