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

• Published in: Diabetes (New York, N.Y.) Vol. 67; no. 7; pp. 1356 - 1368
• Main Authors: Marre, Meghan L., McGinty, John W., Chow, I-Ting, DeNicola, Megan E., Beck, Noah W., Kent, Sally C., Powers, Alvin C., Bottino, Rita, Harlan, David M., Greenbaum, Carla J., Kwok, William W., Piganelli, Jon D., James, Eddie A.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.07.2018
• Subjects: Animals; Antigen Presentation; Autoantigens - immunology; Autoimmunity - immunology; Case-Control Studies; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Endoplasmic Reticulum Stress - physiology; Enzyme Activation; Epitopes, T-Lymphocyte - immunology; Epitopes, T-Lymphocyte - metabolism; GTP-Binding Proteins - metabolism; Humans; Immunology and Transplantation; Insecta; Insulin-Secreting Cells - immunology; Insulin-Secreting Cells - metabolism; Protein Processing, Post-Translational - physiology; Protein-Arginine Deiminase Type 2; Protein-Arginine Deiminases - metabolism; Transglutaminases - metabolism
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db17-1166

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.