# Role of hybrid peptide specific T cells in diabetes

> **NIH NIH P01** · UNIVERSITY OF MINNESOTA · 2022 · $364,861

## Abstract

Summary
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. In preliminary studies, we identified HP-specific CD4+ T cells
using novel tetramer reagents, and showed they can cause T1D in mouse transfer models.
Thus, we hypothesize that HPs are critical antigens and that autoreactivity to HPs initiates T1D.
The deciding factor in whether HP will prime CD4+ T cells to initiate T1D is the inflammatory
context during initial T cell receptor signaling, particularly the timing of type I interferon (IFN-I)
exposure. Aim 1 will utilize mouse strains of varying T1D susceptibilities, and evaluate their
frequency and activation phenotype of HP-specific cells. We predict that targeting hybrid
peptide-specific cells will prevent and possibly reverse T1D, thus confirming their pathogenic
role. Completion of this work will also provide insight into the role of hybrid peptide-specific cells
in human T1D, as we will evaluate the frequency and phenotype of these cells in T1D patients
and at-risk individuals. Aim 2 will test the hypothesis that IFN-I or viral infection(s) concurrent
with TCR signaling leads to T1D, while IFN-I exposure preceding TCR signaling promotes Tregs
and protection from T1D. Finally, we will test tolerance induction using antigen-coupled cells or
novel peptide:MHCII blocking antibodies in normal microbial experience mice to determine if
tolerance can be induced in a physiological environment more closely resembling that of
humans.

## Key facts

- **NIH application ID:** 10466845
- **Project number:** 5P01AI035296-28
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Brian T Fife
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $364,861
- **Award type:** 5
- **Project period:** 1997-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466845

## Citation

> US National Institutes of Health, RePORTER application 10466845, Role of hybrid peptide specific T cells in diabetes (5P01AI035296-28). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10466845. Licensed CC0.

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