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@ARTICLE{Azoury:176904,
author = {M. E. Azoury and F. Samassa and M. Buitinga and L. Nigi and
N. Brusco and A. Callebaut and M. Giraud and M. Irla and A.
I. Lalanne and A. Carré and G. Afonso and Z. Zhou and B.
Brandao and M. L. Colli and G. Sebastiani and F. Dotta and
M. Nakayama and D. L. Eizirik and S. You and S. Pinto$^*$
and M. J. Mamula and Y. Verdier and J. Vinh and S. Buus and
C. Mathieu and L. Overbergh and R. Mallone},
title = {{CD}8+ {T} cells variably recognize native versus
citrullinated {GRP}78 epitopes in type 1 diabetes.},
journal = {Diabetes},
volume = {70},
number = {12},
issn = {1939-327X},
address = {Alexandria, Va},
publisher = {Assoc.},
reportid = {DKFZ-2021-02146},
pages = {2879-2891},
year = {2021},
note = {Deutsches Krebsforschungszentrum (DKFZ), Division of
Developmental Immunology, 69120 Heidelberg, Germany., 2021
Dec;70(12):2879-2891},
abstract = {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.},
cin = {D090 ; D090},
ddc = {610},
cid = {I:(DE-He78)D090-20160331},
pnm = {314 - Immunologie und Krebs (POF4-314)},
pid = {G:(DE-HGF)POF4-314},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:34561224},
doi = {10.2337/db21-0259},
url = {https://inrepo02.dkfz.de/record/176904},
}