# Targeting TH17 cell metabolism in steroid resistance

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $441,535

## Abstract

SUMMARY
Inflammatory diseases are often characterized by imbalanced ratios or functions of T effector (Teff),
such as elevated Th2 and Th17 that promote asthma, and regulatory (Treg) cells, that suppress
inflammation. While many such diseases can be controlled with corticosteroids, some, including
severe asthma and multiple sclerosis, can show steroid (glucocorticoid; GC)-resistance and lead to
increasingly negative outcomes, including death. Understanding factors that promote steroid-
resistance, therefore, is critical to establish new approaches to treat GC-resistant inflammatory
diseases. It is now clear that while Th2 cells are GC sensitive, steroid-resistant asthma is often
characterized by the presence of IL17 producing cells, including Th17 CD4 T cells that can have
intrinsic GC resistance. GC are well known to inhibit metabolism and we propose that the unique
metabolism of Th17 cells contributes to their selective GC resistance. We have shown that T cell
metabolism is dynamic and the Phosphatidylinositide 3-Kinase (PI3K)/Akt/mTOR Complex 1
(mTORC1) pathway induces Th17 CD4 T cells to increase glycolysis and metabolism of glutamine to
glutamate for mitochondrial oxidation (glutaminolysis). Consistent with this metabolic program, we
show allergen challenge increases both lactate and glutamate in bronchalveolar lavage (BAL) fluid of
asthmatics and that T cells from BAL of asthma patients express the glucose transporter Glut1 at high
levels. Importantly, GC resistant Th17 cells have both higher levels of glucose metabolism and
glutaminolysis than GC sensitive Th2 cells. Th17 cells also have higher mitochondrial respiratory
capacity and ability to withstand mitochondrial inhibition than Th2 cells. In contrast, Treg use lipid
oxidation and have high levels of active AMPK, which inhibits mTORC1. Further, we show Treg are
functionally impaired by high rates of glycolysis. We also show that Th17 cells rely on Glutaminase
(GLS) to support glutaminolysis and differentiation, and inhibition of GLS selectively impairs Th17
cells. Elevated levels of glucose and glutamine metabolism may directly protect Th17 cells from GC,
as T cells with increased Glut1 were resistant to GC-induced reactive oxygen species and cell death.
Here we will test the hypothesis that allergen-induced cytokines signal T cells to induce a flexible
metabolism of glycolysis and glutaminolysis that promotes GC resistance in Th17 cells and impairs
Treg. To test this hypothesis we will: (1) Determine T cell metabolic programs and regulatory signals
in airway inflammation and (2) Test the contribution of T cell metabolism to GC resistance of Th17
cells. Together, these studies will address a poorly understood but potentially key contributor to the
pathogenesis of GC-resistant inflammatory diseases, such as severe asthma, by establishing and
targeting the unique metabolic program and requirements of Th17 cells.

## Key facts

- **NIH application ID:** 9856491
- **Project number:** 5R01HL136664-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Jeffrey C Rathmell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,535
- **Award type:** 5
- **Project period:** 2017-04-06 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856491

## Citation

> US National Institutes of Health, RePORTER application 9856491, Targeting TH17 cell metabolism in steroid resistance (5R01HL136664-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856491. Licensed CC0.

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