# Identifying and preventing antigen specific T cells in diabetes

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2022 · $590,331

## Abstract

SUMMARY
Type 1 diabetes (T1D) is an autoimmune disease resulting from a breakdown in immunological
tolerance caused by T cell-mediated destruction of islet beta cells. Diabetes is orchestrated by HLAII-
restricted CD4+ T cells, through cellular interactions with both B cells and CD8+ T cells, resulting in
autoantibody production and beta cell death, respectively. While anti-islet autoantibodies are currently
the best predictors of T1D development, screening is limited to four islet antigens and no T cell
biomarkers exist. Despite years of research, it is still unclear which antigen-specific CD4+ T cells
initiate T1D. New evidence suggests that hybrid peptides (HP) formed from the fusion of islet β cell
proteins may be critical antigens in T1D as recent studies identified HP-reactive CD4+ T cells from
T1D patients and diabetic mice in vitro. These neo-antigens escape central tolerance and must be
controlled by peripheral mechanisms including anergy or regulatory T cell control. In preliminary
studies, we identified HP-specific CD4+ T cells in diabetic mouse models using tetramer reagents,
and showed they are pathogenic and cause T1D in mouse transfer models. More importantly, we can
block spontaneous T1D in the NOD mouse model targeting one hybrid peptide when presented in
mouse MHCII using peptide-specific:MHCII blocking antibodies. Thus, we hypothesize that HPs are
critical antigens and that autoreactivity to HPs initiates T1D. The goals of this proposal are to
determine if HP-specific CD4+ T cells initiate T1D and if targeting them can lead to tolerance as a
prevention or cure for T1D. The second goal of the grant is to determine if HP specific cells are
relevant for human T1D and use of scRNA-seq analysis to uncover critical clues about shared
transcriptional programs related to the pathogenic potential between human and mouse HP reactive
T cells. Completion of this project could lead to better biomarkers to predict T1D risk and disease
progression.

## Key facts

- **NIH application ID:** 10436364
- **Project number:** 5R01AI156276-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Brian T Fife
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $590,331
- **Award type:** 5
- **Project period:** 2021-06-22 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436364

## Citation

> US National Institutes of Health, RePORTER application 10436364, Identifying and preventing antigen specific T cells in diabetes (5R01AI156276-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436364. Licensed CC0.

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