# Identification of the cognate epitopes of autoreactive T cells in Type 1 Diabetes

> **NIH NIH R03** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $153,675

## Abstract

ABSTRACT
Type 1 Diabetes (T1D), affects approximately 4 million individuals worldwide, including 1.6 million Americans.
T1D is caused by progressive destruction of pancreatic  cells, resulting in a significantly diminished capacity to
produce insulin. Diabetogenic CD8+ and CD4+ effector T cells that infiltrate pancreatic islets mediate  cell
destruction in an antigen-specific manner by recognizing peptide epitopes presented on class I and class II MHC
molecules respectively. In contrast, regulatory T cells can suppress diabetogenic T cells, thereby preventing T1D
pathogenesis. Recognition of epitopes presented by  cells is critical for the function of these autoreactive T
cells. Only a small number of self-epitopes recognized by autoreactive CD8+, CD4+ effector and regulatory T
cells in T1D have been uncovered. However, the epitopes recognized by the majority of islet-infiltrating T cells
are not known. The knowledge of these epitopes is critical for understanding disease pathogenesis and for
developing targeted therapies. Currently, widely applicable and efficient methods for T cell antigen discovery for
uncovering autoreactivity are lacking. The overarching goal of this project is to uncover the cognate epitopes of
autoreactive T cells in T1D using a novel and generalizable antigen discovery technology developed by our
group. In this proposal, we will employ T cell epitope discovery using Signaling and Antigen-presenting
Bifunctional Receptors (SABRs) to identify the epitopes recognized by effector and regulatory T cells in a mouse
model of T1D, NOD mice. We propose that constructing a library of epitopes derived from genes expressed
specifically in pancreatic  cells will lead to identification of novel targets of islet-infiltrating T cells. We will
construct epitope libraries from published mass spectrometry and gene expression datasets from NOD mice.
We will obtain islet-reactive TCRs by performing single cell TCR sequencing on pancreatic islets of NOD mice.
Using  cell derived SABR libraries, we will determine the cognate epitopes of islet-reactive TCRs and validate
them in vitro. The epitopes identified by these studies will lead to future studies aiming to understand the
breakage of immune tolerance by autoreactive T cells and to develop targeted immunotherapy approaches to
combat T1D. This approach will also establish the foundation for antigen discovery for T cells from T1D patient
samples in affiliation with Human Islet Research Network.
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## Key facts

- **NIH application ID:** 10132015
- **Project number:** 1R03DK127447-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Alok Joglekar
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $153,675
- **Award type:** 1
- **Project period:** 2020-09-14 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132015

## Citation

> US National Institutes of Health, RePORTER application 10132015, Identification of the cognate epitopes of autoreactive T cells in Type 1 Diabetes (1R03DK127447-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10132015. Licensed CC0.

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