# IFN-y drives Treg fragility through DNA methylation of the Treg-specific de-methylated regions

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $45,520

## Abstract

PROJECT SUMMARY
Regulatory T cells (Tregs) are characterized by expression of master regulator, Foxp3, and their ability to limit
autoimmunity and maintain peripheral tolerance. However, these cells also play a deleterious role in suppressing
the anti-tumor response. Our lab found that deletion of neuropilin-1 (Nrp1) on Tregs results in decreased
suppression of the anti-tumor response without compromising peripheral tolerance. We also found that these
cells change their phenotype, such as secretion of IFN and loss of suppressive capability, but maintain Foxp3
expression, which we coined as Treg fragility. We have also shown that IFN-mediated Treg fragility is required for
a productive immunotherapeutic response to anti-PD1 immune checkpoint blockade in mice. Interestingly, we
found that IFN causes DNA methylation of an enhancer element that exists in the Foxp3 locus, the conserved
non-coding sequence 2, or CNS2 in vitro. We do not yet know if IFN causes re-methylation of other Treg-specific
de-methylated regions (TSDRs). It is possible that this re-methylation could contribute to Treg fragility.
This research proposes to elucidate how IFN contributes to Treg fragility in two specific aims. First, it would be
of interest to understand how IFN-mediated DNA re-methylation occurs. We will examine if downstream
modulator STAT1 can modulate levels of the DNA methyltransferase enzymes (DNMT1, DNMT3a, and
DNMT3b) as well as differential binding to TSDR loci.
Next, we will elucidate if IFN causes re-methylation of TSDR loci in vivo after anti-PD1 therapy. Moreover, we
will elucidate if CD8 T cells are the source of the IFN after treatment. These proposed studies will give insight
on the mechanisms of Treg fragility.

## Key facts

- **NIH application ID:** 9969037
- **Project number:** 5F31CA236337-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Rebekah Dadey
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969037

## Citation

> US National Institutes of Health, RePORTER application 9969037, IFN-y drives Treg fragility through DNA methylation of the Treg-specific de-methylated regions (5F31CA236337-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9969037. Licensed CC0.

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