# Transcriptional and metabolic regulation of Treg cell specification for the control of allergic airway disease

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $447,387

## Abstract

PROJECT SUMMARY
Acquisition of the TH2 suppressor program specializes Treg cell function in preventing the development of allergic
airway inflammation associated with asthma. Airway allergic responses arise when there is ineffective
development of tolerance to normally harmless environmental antigens and activation of pro-allergic TH2
responses. Cooperation of Foxp3 with additional transcription factors is crucial for establishing this specific
function. Aside from the transcriptional regulation, reprogramming of cellular metabolism represents an important
regulatory mechanism underlying Treg cell homeostasis and function. However, it remains elusive how Treg
cells coordinate immune signaling and cellular metabolism with Treg cell functional specification in the control of
allergic airway disease (AAD). We recently demonstrated that liver kinase B1 (LKB1), an important regulator of
cellular metabolism, is indispensable for Treg cells in suppressing allergic airway inflammation. In our preliminary
studies, we found that loss of LKB1 resulted in impaired expression of BATF and function of IRF4 in Treg cells.
By generating a new mouse model with Treg-specific ablation of BATF, we revealed that BATF-deficient Treg
cells selectively lost their capabilities of restraining TH2-mediated lung inflammation. Moreover, we observed that
lung-resident Treg cells displayed higher levels of cellular triacylglycerols (TAGs) than splenic Treg cells from
mice with lung inflammation. Loss of LKB1 and BATF in Treg cells enhanced biosynthesis of unsaturated fatty
acids (UFAs) and TAGs, both associated with increased expression of SCD1 and DGAT2, the rate-limiting
enzymes for synthesis of UFAs and TAGs, respectively. Finally, suppressing SCD1 and DGAT2 reduced levels
of cellular lipids and concomitantly increased Foxp3 expression. We hypothesize that LKB1 signaling links
activation of a BATF/IRF4-dependent transcriptome and regulation of UFA and TAG biosynthesis with Treg cell
functional specification for the control of allergic airway disease. Specifically, we will test this hypothesis in two
specific Aims: (1) Determine how the LKB1-BATF/IRF4 axis orchestrates the TH2 suppressor program in Treg
cells for the control of allergic airway disease; (2) Determine if regulation of UFA and TAG biosynthesis alters
Treg cell function in preventing AAD. Studies from this application may advance our understanding of how Treg
cells coordinate transcriptional activation and regulation of lipid biosynthesis in orchestrating the TH2 suppressor
program and manifest therapeutic opportunities for treating AAD.

## Key facts

- **NIH application ID:** 10296743
- **Project number:** 1R01AI153255-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Kai Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $447,387
- **Award type:** 1
- **Project period:** 2021-05-18 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296743

## Citation

> US National Institutes of Health, RePORTER application 10296743, Transcriptional and metabolic regulation of Treg cell specification for the control of allergic airway disease (1R01AI153255-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10296743. Licensed CC0.

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