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000176904 0247_ $$2doi$$a10.2337/db21-0259
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000176904 037__ $$aDKFZ-2021-02146
000176904 041__ $$aEnglish
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000176904 1001_ $$aAzoury, Marie Eliane$$b0
000176904 245__ $$aCD8+ T cells variably recognize native versus citrullinated GRP78 epitopes in type 1 diabetes.
000176904 260__ $$aAlexandria, Va$$bAssoc.$$c2021
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000176904 500__ $$aDeutsches Krebsforschungszentrum (DKFZ), Division of Developmental Immunology, 69120 Heidelberg, Germany., 2021 Dec;70(12):2879-2891
000176904 520__ $$aIn 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.
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000176904 7001_ $$aSamassa, Fatoumata$$b1
000176904 7001_ $$aBuitinga, Mijke$$b2
000176904 7001_ $$aNigi, Laura$$b3
000176904 7001_ $$aBrusco, Noemi$$b4
000176904 7001_ $$aCallebaut, Aïsha$$b5
000176904 7001_ $$aGiraud, Matthieu$$b6
000176904 7001_ $$aIrla, Magali$$b7
000176904 7001_ $$aLalanne, Ana Ines$$b8
000176904 7001_ $$aCarré, Alexia$$b9
000176904 7001_ $$aAfonso, Georgia$$b10
000176904 7001_ $$aZhou, Zhicheng$$b11
000176904 7001_ $$aBrandao, Barbara$$b12
000176904 7001_ $$aColli, Maikel L$$b13
000176904 7001_ $$aSebastiani, Guido$$b14
000176904 7001_ $$aDotta, Francesco$$b15
000176904 7001_ $$aNakayama, Maki$$b16
000176904 7001_ $$aEizirik, Decio L$$b17
000176904 7001_ $$aYou, Sylvaine$$b18
000176904 7001_ $$0P:(DE-He78)d2f9dbffa7b9a979f9bc4d81e769497e$$aPinto, Sheena$$b19
000176904 7001_ $$aMamula, Mark J$$b20
000176904 7001_ $$aVerdier, Yann$$b21
000176904 7001_ $$aVinh, Joelle$$b22
000176904 7001_ $$aBuus, Soren$$b23
000176904 7001_ $$aMathieu, Chantal$$b24
000176904 7001_ $$aOverbergh, Lut$$b25
000176904 7001_ $$aMallone, Roberto$$b26
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