# Metabolic control of regulatory T cells during metabolic stress caused by viral pneumonia

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2022 · $46,752

## Abstract

PROJECT SUMMARY
Regulatory T (Treg) cells are a subset of CD4+ T cells that maintain immune self-tolerance and mediate recovery
from viral pneumonia by resolving lung inflammation and orchestrating tissue repair after lung injury. Treg cells
also display metabolic plasticity; they modulate which substrates they acquire and how they metabolize them to
support their functions in metabolically stressful microenvironments. AMP-activated Protein Kinase (AMPK)
serves as a master regulator metabolic homeostasis by inducing energy-replenishing processes during energetic
stress. AMPK promotes mitochondrial biogenesis (via epigenetic induction of the mitochondrial mass-promoting
molecule PGC-1α) and long-chain fatty acid oxidation (LC-FAO, via activation of the mitochondrial LC-FA
importer CPT1) in states of energy depletion. Treg cells have high levels of AMPK, and pharmacologic activation
of AMPK induces Treg cell generation in vitro and in mouse models of lung disease. Surprisingly, Treg cell-
specific loss of AMPK in vivo does not lead to spontaneous lethal autoimmunity or other signs of Treg cell dys-
function, suggesting that AMPK is redundant in Treg cells at homeostatic conditions. To explore the role of AMPK
in the Treg cell response to pathologies associated with metabolic stress (nutrient depletion, hypoxia, and
oxidative stress), we bred Treg cell-specific AMPK knockout (Treg AMPK KO) mice and challenged them with
either intratracheal instillation of influenza virus or subcutaneous engraftment of B16 melanoma tumors. While
influenza virus-inoculated Treg AMPK KO mice had lower survival, tumors of Treg AMPK KO mice exhibited
impaired growth and smaller volumes relative to controls. These results suggest that AMPK-deficient Treg cells
undergo loss-of-function in settings of pathology-induced metabolic stress. Therefore, we hypothesize that Treg
cell AMPK-mediated induction of mitochondrial mass and LC-FA oxidation are required for their pro-recovery
function during influenza pneumonia. To elucidate the causal mechanisms through which AMPK promotes Treg
cell pro-recovery function in the injured lung, we will leverage mice with Treg cell-specific deficiency of either
AMPK and CPT1, along with influenza virus infection as a murine model of viral pneumonia. Our Specific Aims
are to determine 1) whether AMPK promotes Treg cell pro-recovery function following influenza pneumonia by
creating a permissive DNA hypomethylation landscape at Ppargc1a (encodes PGC-1α) to sustain their
mitochondrial mass, and 2) whether AMPK-dependent mitochondrial import of LC-FAs is required for Treg cell
pro-recovery function following influenza pneumonia. The PI's excellent mentorship network consists of
experienced scientists in the fields of immunology, epigenetics, metabolism, and lung disease, all of whom will
provide both day-to-day and high-level support during the funding period. The PI's environment is outstanding,
with all necessary facilities, equipment, and expe...

## Key facts

- **NIH application ID:** 10537166
- **Project number:** 1F31HL162490-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Manuel Andrés Torres Acosta
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537166

## Citation

> US National Institutes of Health, RePORTER application 10537166, Metabolic control of regulatory T cells during metabolic stress caused by viral pneumonia (1F31HL162490-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10537166. Licensed CC0.

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