# Project 2 - Specificity and repertoire of Tregs in T1D

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $382,872

## Abstract

Project Summary/Abstract 
Type 1 Diabetes (T1D) is caused by pathogenic autoreactive T cells that recognize and destroy the islet tissue. 
However, the presence of T cells reactive to self-antigens is not sufficient for disease to occur as autoreactive 
T cells can be found in healthy control subjects; thus various means are available that control unwanted 
responses. One of the most important mechanisms is the activity of regulatory T cells (Tregs), which arise both 
in thymus and in the peripheral immune system as a consequence of exposure to antigens. Defects in Treg 
numbers, phenotype, and/or function have been described in T1D and other autoimmune diseases. Because 
immunosuppression by Tregs specific for a limited number of Ags is dominant and can efficiently thwart a 
polyclonal autoreactive response, Tregs are an attractive target for antigen-specific tolerogenic therapies. 
However, the specificity and repertoire of Tregs recognizing self-Ags in humans and mice and whether 
they are different in individuals with autoimmunity is unknown. 
Recent studies have uncovered unique aspects of self-peptides presentation to autoreactive T cells by MHC 
class II alleles predisposing to autoimmunity. These peculiarities potentially circumvent negative selection of 
autoreactive T cells in the thymus and lead to autoreactivity in the target tissue. Given the well-known skewing 
of the tTreg repertoire towards self-reactivity, biochemical complexities may affect the development and 
repertoire of Tregs and their ability to recognize self-Ags in the targeted tissues – suggesting that the Ag 
specificity of local Tregs will be instrumental in controlling autoimmunity in the tissue. Thus, identifying the Ag 
specificity of Tregs, especially at the site of inflammation, is critical to improve our understanding of Treg 
deficiencies in T1D. In this project, we will address this question by examining the overall hypothesis that the 
biochemical intricacies that promote effector immunity may paradoxically alter Treg efficacy and 
contribute to the overall failure of Tregs to control autoreactive Tconv cells in autoimmune diseases 
such as T1D. We propose the following Specific Aims to address this question: 1: Characterization of Treg 
specificity against known I-Ag7-restricted autoantigens 2: Antigen focused approach to define the 
specificity of Tregs in T1D patients. 3: Identification of novel ligands for Tregs in NOD mice and T1D 
patients. 
It is recognized that altered Treg immunoregulation is an inherent factor in autoimmunity but defining specific 
Treg defects in T1D patients has been challenging. Thus, defining the specificity and repertoire of Tregs and 
their reactive TCRs would be an important step towards the discovery of selective Treg defects in T1D and 
greatly improve our understanding of the immunopathology of disease. Moreover, it would pave the way for 
therapeutic opportunities aimed at restoring proper Treg immunoregulation in pancrea...

## Key facts

- **NIH application ID:** 9942372
- **Project number:** 5P01AI118688-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JEFFREY A BLUESTONE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,872
- **Award type:** 5
- **Project period:** — → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942372

## Citation

> US National Institutes of Health, RePORTER application 9942372, Project 2 - Specificity and repertoire of Tregs in T1D (5P01AI118688-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9942372. Licensed CC0.

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