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CD8+ T Cells Variably Recognize Native versus Citrullinated GRP78 Epitopes in Type 1 Diabetes

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posted on 24.09.2021, 16:26 by Marie Eliane Azoury, Fatoumata Samassa, Mijke Buitinga, Laura Nigi, Noemi Brusco, Aïsha Callebaut, Matthieu Giraud, Magali Irla, Ana Ines Lalanne, Alexia Carré, Georgia Afonso, Zhicheng Zhou, Barbara Brandao, Maikel L. Colli, Guido Sebastiani, Francesco Dotta, Maki Nakayama, Decio L. Eizirik, Sylvaine You, Sheena Pinto, Mark J. Mamula, Yann Verdier, Joelle Vinh, Soren Buus, Chantal Mathieu, Lut Overbergh, Roberto Mallone
In type 1 diabetes, autoimmune β-cell destruction may be favored by neo-antigens harboring post-translational modifications such as citrullination. We studied the recognition of native and citrullinated glucose-regulated protein (GRP)78 peptides by CD8+ T cells. Citrullination modulated T-cell recognition and, to a lesser extent, HLA-A2 binding. GRP78-reactive CD8+ T cells circulated at similar frequencies in type 1 diabetic and healthy donors and preferentially recognized either native or citrullinated versions, without cross-reactivity. Rather, the preference for native GRP78 epitopes was associated with CD8+ T cells cross-reactive with bacterial mimotopes. In the pancreas, a dominant GRP78 peptide was instead preferentially recognized when citrullinated. To further clarify these recognition patterns, we considered the possibility of citrullination in the thymus. Citrullinating peptidyl-arginine deiminase (Padi) enzymes were expressed in murine and human medullary epithelial cells (mTECs), with citrullinated proteins detected in murine mTECs. However, Padi2 and Padi4 expression was diminished in mature mTECs from NOD mice versus C57BL/6 mice. We conclude that, on one hand, the CD8+ T-cell preference for native GRP78 peptides may be shaped by cross-reactivity with bacterial mimotopes. On the other hand, post-translational modifications may not invariably favor loss of tolerance because thymic citrullination, although impaired in NOD mice, may drive deletion of citrulline-reactive T cells.


This work was supported by JDRF grants 2-SRA-2016-164-Q-R (to R.M.), 2-SRA-2015-52-Q-R (to C.M. and L.O.), 2-SRA-2018-480-S-B (to M.N.) and Postdoctoral Fellowship 3-PDF-2020-942-A-N (to Z.Z.); The Leona M. and Harry B. Helmsley Charitable Trust (Helmsley #1901-03689), the Fondation Francophone pour la Recherche sur le Diabète (FFRD), the EFSD/JDRF/Lilly European Programme in Type 1 Diabetes Research 2015, the Agence Nationale de la Recherche (ANR-19-CE15-0014-01) and the Fondation pour la Recherche Medicale (EQU20193007831), to R.M.; and the NIDDK (R01DK099317, R01DK032083), to M.N.. M.B. and Aï.Ca. were supported by a fellowship from the Flemish Research Foundation (12R0719N and 1189518N, respectively). F.D., D.L.E., C.M., L.O. and R.M. received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreements 115797 and 945268 (INNODIA and INNODIA HARVEST), which receive support from the EU Horizon 2020 program, the European Federation of Pharmaceutical Industries and Associations, JDRF, and The Leona M. & 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 sponsored by JDRF (nPOD: 5-SRA-2018-557-Q-R) and The Leona M. & Harry B. Helmsley Charitable Trust (Grant #2018PG-T1D053). Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at The content and views expressed are the responsibility of the authors and do not necessarily reflect an official view of nPOD.