TY  - JOUR
AU  - Azoury, Marie Eliane
AU  - Samassa, Fatoumata
AU  - Buitinga, Mijke
AU  - Nigi, Laura
AU  - Brusco, Noemi
AU  - Callebaut, Aïsha
AU  - Giraud, Matthieu
AU  - Irla, Magali
AU  - Lalanne, Ana Ines
AU  - Carré, Alexia
AU  - Afonso, Georgia
AU  - Zhou, Zhicheng
AU  - Brandao, Barbara
AU  - Colli, Maikel L
AU  - Sebastiani, Guido
AU  - Dotta, Francesco
AU  - Nakayama, Maki
AU  - Eizirik, Decio L
AU  - You, Sylvaine
AU  - Pinto, Sheena
AU  - Mamula, Mark J
AU  - Verdier, Yann
AU  - Vinh, Joelle
AU  - Buus, Soren
AU  - Mathieu, Chantal
AU  - Overbergh, Lut
AU  - Mallone, Roberto
TI  - CD8+ T cells variably recognize native versus citrullinated GRP78 epitopes in type 1 diabetes.
JO  - Diabetes
VL  - 70
IS  - 12
SN  - 1939-327X
CY  - Alexandria, Va
PB  - Assoc.
M1  - DKFZ-2021-02146
SP  - 2879-2891
PY  - 2021
N1  - Deutsches Krebsforschungszentrum (DKFZ), Division of Developmental Immunology, 69120 Heidelberg, Germany., 2021 Dec;70(12):2879-2891
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:34561224
DO  - DOI:10.2337/db21-0259
UR  - https://inrepo02.dkfz.de/record/176904
ER  -