American Diabetes Association
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CD4+ T cells from individuals with type 1 diabetes respond to a novel class of deamidated peptides formed in pancreatic islets

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Version 2 2024-03-07, 16:53
Version 1 2024-02-22, 21:57
posted on 2024-03-07, 16:53 authored by Aїsha Callebaut, Perrin Guyer, Rita Derua, Mijke Buitinga, Anthony Manganaro, Xiaoyan Yi, Fernanda Marques Câmara Sodré, Saurabh Vig, Mara Suleiman, Piero Marchetti, Decio L. Eizirik, Sally C. Kent, Chantal Mathieu, Eddie A. James, Lut Overbergh

The β-cell plays a crucial role in the pathogenesis of type 1 diabetes, in part through the post-translational modification of self-proteins by biochemical processes such as deamidation. These neoantigens are potential triggers for breaking immune tolerance. We report the detection by LC-MS/MS of 16 novel Gln and 27 novel Asn deamidations in 14 disease-related proteins within inflammatory cytokine-stressed human islets of Langerhans. T-cell clones responsive against one Gln and three Asn deamidated peptides could be isolated from peripheral blood of individuals with type 1 diabetes. Ex vivo HLA class II tetramer staining detected higher T-cell frequencies in individuals with the disease compared to control individuals. Furthermore, there was a positive correlation between the frequencies of T cells specific for deamidated peptides, insulin antibody levels at diagnosis, and duration of disease. These results highlight that stressed human islets are prone to enzymatic and biochemical deamidation and suggest that both Gln and Asn deamidated peptides can promote the activation and expansion of autoreactive CD4+ T cells. These findings add to the growing evidence that post-translational modifications undermine tolerance and may open the road for the development of new diagnostic and therapeutic applications for individuals living with type 1 diabetes.


This work was supported by IMI2-JU under grant agreement No 115797 (INNODIA) and No 948268 (INNODIA HARVEST). This joint undertaking received support from the Union’s Horizon 2020 research and innovation program and through the EFPIA, JDRF, and The Leona M. and Harry B. Helmsley Charitable Trust. This research was performed with the support of the Network for Pancreatic Organ donors with Diabetes (nPOD; RRID:SCR_014641), a collaborative type 1 diabetes research project supported by the JDRF (nPOD: 5-SRA-2018-557-Q-R) and The Leona M. & Harry B. Helmsley Charitable Tust (Grant#2018PG-T1D053, G-2108-04793). The content and views expressed are the responsibility of the authors and do not necessarily reflect the official view of nPOD. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at The work was funded by the KU Leuven (C16/18/006), the Flemish Research Foundation (a predoctoral fellowship for A.C. (1189518N) and a postdoctoral fellowship for M.B. (3-PDF-2018-593-A-N)), and JDRF 2-SRA-2018-551-S-B to E.A.J.


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