Open AccessThe MHC-II peptidome of pancreatic islets identifies key features of autoimmune peptides
Author(s) -
Xiaoxiao Wan,
Anthony N. Vomund,
Orion J. Peterson,
Alexander V. Chervonsky,
Cheryl F. Lichti,
Emil R. Unanue
Publication year - 2020
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-020-0623-7
Subject(s) - major histocompatibility complex , proinsulin , nod mice , pancreatic islets , autoimmune diabetes , mhc class ii , antigen presentation , immunology , mhc class i , epitope , biology , autoimmunity , antigen , islet , immune system , diabetes mellitus , t cell , endocrinology
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 major histocompatibility complex class II (MHC-II) molecule. Here, we examined the immunopeptidome of the pancreatic islets in non-obese diabetic mice, which spontaneously develop autoimmune diabetes based on the I-A g7 variant of MHC-II. The relevant peptides that induced pathogenic CD4 + T cells at the initiation of diabetes derived from proinsulin. These peptides were also found in the MHC-II peptidome of the pancreatic lymph nodes and spleen. The proinsulin-derived peptides followed a trajectory from their generation and exocytosis in β cells to uptake and presentation in islets and peripheral sites. Such a pathway generated conventional epitopes but also resulted in the presentation of post-translationally modified peptides, including deamidated sequences. These analyses reveal the key features of a restricted component in the self-MHC-II peptidome that caused autoreactivity.