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Diabetes. 2018 Jul;67(7):1356-1368. doi: 10.2337/db17-1166. Epub 2018 Apr 13.

Modifying Enzymes Are Elicited by ER Stress, Generating Epitopes That Are Selectively Recognized by CD4+ T Cells in Patients With Type 1 Diabetes.

Author information

1
Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA.
2
Benaroya Research Institute at Virginia Mason, Seattle, WA.
3
Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA.
4
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN.
5
VA Tennessee Valley Healthcare System, Nashville, TN.
6
Islet Isolation Laboratory, Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA.
7
Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA.
8
Department of Medicine, University of Washington, Seattle, WA.
9
Benaroya Research Institute at Virginia Mason, Seattle, WA ejames@benaroyaresearch.org.

Abstract

In spite of tolerance mechanisms, some individuals develop T-cell-mediated autoimmunity. Posttranslational modifications that increase the affinity of epitope presentation and/or recognition represent one means through which self-tolerance mechanisms can be circumvented. We investigated T-cell recognition of peptides that correspond to modified β-cell antigens in subjects with type 1 diabetes. Modified peptides elicited enhanced proliferation by autoreactive T-cell clones. Endoplasmic reticulum (ER) stress in insulinoma cells increased cytosolic calcium and the activity of tissue transglutaminase 2 (tTG2). Furthermore, stressed human islets and insulinomas elicited effector responses from T cells specific for modified peptides, suggesting that ER stress-derived tTG2 activity generated deamidated neoepitopes that autoreactive T cells recognized. Patients with type 1 diabetes had large numbers of T cells specific for these epitopes in their peripheral blood. T cells with these specificities were also isolated from the pancreatic draining lymph nodes of cadaveric donors with established diabetes. Together, these results suggest that self-antigens are enzymatically modified in β-cells during ER stress, giving rise to modified epitopes that could serve to initiate autoimmunity or to further broaden the antigenic repertoire, activating potentially pathogenic CD4+ T cells that may not be effectively eliminated by negative selection.

PMID:
29654212
PMCID:
PMC6014552
[Available on 2019-07-01]
DOI:
10.2337/db17-1166
[Indexed for MEDLINE]

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