Aberrant expression of transglutaminase 2 in pancreas and thymus of NOD mice underscores the importance of deamidation in neoantigen generation

Abstract

Post-translational modifications can lead to a break in immune tolerance in autoimmune diseases such as type 1 diabetes (T1D). Deamidation, the conversion of glutamine to glutamic acid by transglutaminase (TGM) enzymes, is a post-translational modification of interest, with deamidated peptides being reported as autoantigens in T1D. However, little is known about how <i>Tgm2</i>, the most ubiquitously expressed <i>Tgm</i> isoform, is regulated and how tolerance against deamidated peptides is lost. Here, we report on the aberrant expression and regulation of <i>Tgm2</i> in the pancreas and thymus of NOD mice. We demonstrate that <i>Tgm2</i> expression is induced by the inflammatory cytokines IL1β and IFNγ in a synergistic manner and that murine pancreatic islets of NOD mice have higher <i>Tgm2</i> levels, while <i>Tgm2</i> levels in medullary thymic epithelial cells are reduced. We thus provide the first direct evidence to our knowledge that central tolerance establishment against deamidated peptides might be impaired due to lower <i>Tgm2</i> expression in NOD medullary thymic epithelial cells, which together with the aberrantly high levels of deamidated peptides in NOD β-cells underscores the role of deamidation in amplifying T-cell reactivity.