The pancreatic islet MHC-II peptidome identifies key features of autoimmune peptides

ABSTRACT: The nature of autoantigens that trigger autoimmune diseases has been much discussed but direct biochemical identification is lacking for most. Addressing this question demands unbiased examination of the self-peptides displayed by a defined autoimmune MHC-II molecule. We have examined the immunopeptidome of the pancreatic islets of the NOD mouse that spontaneously develops autoimmune diabetes based on its MHC-II, the I-Ag7 variant. The relevant peptides that induced early CD4 T cells derived from insulin and C-peptide; these were also found in the MHC-II peptidome of the pancreatic lymph node and spleen. The insulin-derived peptides followed a trajectory from internal processing in beta cells to exocytosis, uptake, and presentation in islets and peripheral sites. Such process not only generated conventional epitopes but also resulted in presentation of post-translationally modified peptides, including deamidated and fused sequences. These analyses reveal the key features of a restricted component in the self-MHC-II peptidome causing autoreactivity.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Pancreatic Islet, Spleen, B Cell, Lymph Node

DISEASE(S): Type 1 Diabetes Mellitus

SUBMITTER: Cheryl Lichti  

LAB HEAD: Cheryl Lichti

PROVIDER: PXD015408 | Pride | 2020-03-12

REPOSITORIES: Pride