# Control of dysfunctional Tregs

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2021 · $484,500

## Abstract

Project Summary
Rejection remains a major hurdle to long lasting transplant survival and we aspire to uncover the
fundamental mechanisms that hinder stable allograft survival. In the last funding period, we studied the
mechanisms of Treg dysfunctions and identified BATF and BATF3 as potent repressors of Foxp3,
suppressing Foxp3 expression and Treg induction. These studies also led to the discovery of the DHX15
helicase as a critical regulator of Foxp3+Tregs, as conditional deletion of Dhx15 in Tregs resulted in a
profound depletion of Tregs in the periphery and lethal autoimmune diseases. In essence, DHX15 is an
RNA helicase (an RNA binding motor protein) and traditionally thought to be involved in RNA processing. Its
roles in the control of Tregs are unexpected and clearly reveal novel previously unknown aspects of Tregs
that are different from currently known mechanisms, and uncovering those mechanisms is the central goal
of this proposal.
Our working hypothesis is that DHX15 controls Treg identity and/or survival at peripheral sites and that its
deficiency results in either their reversion to Teff or die of apoptosis. We surmise that DHX15 may also
control Tregs at the graft site, where they must overcome the inflammatory milieu to exert suppressive
functions. We proposed 3 Aims to test this hypothesis in this application: the first Aim is to test whether
DHX15 controls Treg identity by acting as an RNA splicing factor, processing mRNAs that encode the
Foxp3 or Foxp3 controlled signature molecules in Tregs, the second Aim is to address whether DHX15
controls Tregs survival by regulating the IL-2 signaling complex, such that Tregs die of apoptosis in its
absence, and the third Aim is to examine whether DHX15 is especially important for Tregs at graft sites
where they are needed the most in promoting transplant tolerance. Overall, DHX15 is the first RNA helicase
identified thus far that controls Tregs, and the genetically modified models as well as cutting-edge
approaches we have developed put us in a unique position in dissecting mechanistically how the DHX15
helicase acts in regulating Tregs, an area of considerable importance in both basic Treg biology and Treg-
based therapies.

## Key facts

- **NIH application ID:** 10217440
- **Project number:** 2R01AI106200-06
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Xian Chang Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $484,500
- **Award type:** 2
- **Project period:** 2014-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217440

## Citation

> US National Institutes of Health, RePORTER application 10217440, Control of dysfunctional Tregs (2R01AI106200-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10217440. Licensed CC0.

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