# Project 1 - Central thymic tolerance as a major checkpoint in T1D

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $373,649

## Abstract

Project Summary/Abstract 
As the site of both negative selection of developing thymocytes and generation of regulatory T cells (Tregs), 
the thymus plays a critical role in the multi-layered network of immune tolerance. The fate of a developing T 
cell is dependent on the affinity of the interaction between the TCR and the peptide-MHC complex it 
recognizes, with the highest affinity interactions resulting in deletion or Treg induction and lower affinity 
interactions resulting in T cell survival and differentiation. The Autoimmune Regulator (Aire) is a major 
transcriptional regulator of peripheral self-antigen expression within the thymus, and loss of Aire leads to 
defects in negative selection due to reduced or absent thymic antigen expression in specialized medullary 
thymic epithelial cells (mTECs). Several lines of evidence point to this process as playing an important role in 
the pathogenesis of type 1 diabetes. Here, we will use type 1 diabetes as a model disease system to further 
unravel how insulin-specific T cells arise from the thymus that are both T effectors and T regulatory cells. 
Our specific aims are: 
AIM1: Define the role of Aire and thymic insulin expression on the thymic deletion of insB(9-23) specific T cells. 
AIM2: Define the repertoire and specificity of thymic Foxp3+ T regulatory cells selected by Aire-expressing 
cells. 
These studies will be performed in close collaboration with PPG projects 2 (Bluestone) and 3 (Kappler) and 
will help improve our understanding of how the T cell repertoire is shaped in the thymus in the setting of type 1 
diabetes.

## Key facts

- **NIH application ID:** 9942371
- **Project number:** 5P01AI118688-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Mark S Anderson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,649
- **Award type:** 5
- **Project period:** — → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942371

## Citation

> US National Institutes of Health, RePORTER application 9942371, Project 1 - Central thymic tolerance as a major checkpoint in T1D (5P01AI118688-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9942371. Licensed CC0.

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