# Characterization of disulfide modified diabetogenic neoepitopes

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $438,463

## Abstract

SUMMARY
Polymorphisms within major histocompatibility complex class II (MHC II) genes confer significant risk for
developing type 1 diabetes (T1D) in both murine models and humans. MHC class II molecules function to present
processed antigens to CD4 T cells, and recent studies have identified a number of different post-translational
modifications (PTM) of self-antigens in T1D including peptide fusion, deamidation, citrullination, and disulfide
bond formation (S-S). Autoimmune T cell responses to neoantigens formed in peripheral tissues may explain
how and why T cell responses are not subject to usual thymic education and tolerance mechanisms. Disulfide
bond formation is an important PTM, with implications for structure, function, and stability of numerous proteins.
We have shown that an epitope from islet amyloid polypeptide (IAPP), which is co-secreted with insulin by
pancreatic beta cells, forms a disulfide bond that activates diabetogenic CD4 T cells when presented by the non-
obese diabetic mouse (NOD) MHC class II molecule, IAg7. Our overarching goal is to study the pathogenicity of
CD4 T cells responding to disulfide modified self-peptides in mouse and human T1D. The first 20 amino acids
of IAPP, termed, is the target antigen for a highly diabetogenic CD4 T cell clone, BDC-5.2.9. KS20-reactive CD4
T cells can be detected in the pancreatic islets of prediabetic and diabetic NOD mice. We showed that the KS20
N-terminal disulfide loop contributes to a large portion of TCR contact, necessary for T cell activation. Increasing
evidence indicates that pancreatic beta-cells undergo oxidative and endoplasmic reticulum stress during T1D
development that can lead to the generation of reactive oxygen species (ROS), which are capable of inducing
post-translational modifications including disulfide bond formation. Thus a potential mechanism exists to form
disulfide modified antigens within pancreatic beta-cells that are capable of activating diabetogenic CD4 T cells.
Taken together, this leads us to hypothesize that disulfide bonds are a common post-translational modification
formed during T1D development that activate islet-antigen specific CD4 T cells. Understanding T cell responses
to disulfide modified antigens will enhance our understanding of T1D disease development and identify
therapeutic targets to prevent tissue-specific disulfide bond formation and potentially prevent T1D. We propose
to determine epitopes for disulfide-reactive CD4 T cells and their necessity for NOD diabetes development and
identify T cells responding to disulfide modified self-antigens in patients at-risk and with newly diagnosed type 1
diabetes.

## Key facts

- **NIH application ID:** 10891719
- **Project number:** 5R01DK137056-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** SHAODONG DAI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $438,463
- **Award type:** 5
- **Project period:** 2023-07-20 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891719

## Citation

> US National Institutes of Health, RePORTER application 10891719, Characterization of disulfide modified diabetogenic neoepitopes (5R01DK137056-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10891719. Licensed CC0.

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