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<sup>+</sup> T cells. Citrullination modulated T-cell recognition
and, to a lesser extent, HLA-A2 binding. GRP78-reactive CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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.