Journal
DIABETES
Volume 67, Issue 7, Pages 1356-1368Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db17-1166
Keywords
-
Categories
Funding
- JDRF [3-PDF-2014-213-A-N, 2-SRA-2016-149, 2-SRA-2014-296-Q-R, 17-2012-121, 2-SRA-2014-297-Q-R]
- Leona M. and Harry B. Helmsley Charitable Trust [2015PG-T1D057]
- National Institutes of Health [R21 AI126189, DK104211, DK106755]
- Human Islet Research Network (HIRN) Opportunity Pool Fund (National Institutes of Health) [U01 DK104162]
- U.S. Department of Veterans Affairs [BX000666]
- Vanderbilt Diabetes Research and Training Center (National Institutes of Health) [DK020593]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R21AI126189] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [UC4DK104211, R24DK106755, P30DK020593, P30DK017047, P60DK020593, UC4DK116284, U01DK104162] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX000666] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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 -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 -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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available