# Transcriptional control of T cell function during type 1 diabetes

> **NIH NIH K01** · NATIONAL JEWISH HEALTH · 2024 · $116,126

## Abstract

PROJECT SUMMARY
T cells responding to persistent antigen during cancer and chronic infection develop a hyporesponsive
phenotype, while T cells responding to self-antigen during type 1 diabetes (T1D) maintain function and eliminate
pancreatic beta cells. My co-mentor previously identified a transcriptional program induced by persistent
stimulation that was shared by mouse and human T cells responding to chronic viral infections and tumors. This
program was linked to the Nuclear Factor of Activated T cells (NFAT) and Nuclear Receptor Subfamily 4 Group
A (NR4A) families of transcription factors (TFs), which are potently induced during chronic stimulation. This
transcriptional program elicited a characteristic pattern of inhibitory receptor expression and also directly reduced
expression of genes encoding effector proteins. In new preliminary studies, I found that only a subset of T cells
specific for self-antigen in the pancreas of NOD mice induced this exhaustion associated transcriptional program.
Cells with increased levels of exhaustion associated TFs had lower expression of genes encoding effector
proteins. These data indicate that the canonical exhaustion program is weakly induced in the autoreactive T cell
pool during diabetes and is a potential target to lessen effects of T cells during autoimmune disease. Based on
these data, my central hypothesis is that expression and activity of the exhaustion program determines the
function of self- antigen specific CD8+ T cells during type 1 diabetes. I predict that 1) the exhaustion associated
program can be activated to limit autoreactive T cell function and 2) the induction of this program is determined
by TCR affinity for self-antigen. I propose two aims to test these predictions during T1D using NOD mice and
human T cells. The expected results of this study will address unanswered questions about the fundamental
mechanisms controlling T cell activity during autoimmune disease and determine the potential to limit
autoimmune disease by controlling exhaustion associated transcriptional programs.

## Key facts

- **NIH application ID:** 10808621
- **Project number:** 1K01DK134835-01A1
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Laura Shaw
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $116,126
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808621

## Citation

> US National Institutes of Health, RePORTER application 10808621, Transcriptional control of T cell function during type 1 diabetes (1K01DK134835-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10808621. Licensed CC0.

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