# Exploiting metabolic vulnerabilities of CD4 T cell subsets to control inflammatory disease

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $381,330

## Abstract

Inflammatory diseases are often caused by inappropriate responses of effector CD4 T cells (Teff). Th17
Teff are IL17-producing CD4 T cells that contribute to a variety of immune pathologies, including Inflammatory
Bowel Disease (IBD). Regulatory T cells (Treg), in contrast, suppress Teff to protect from disease. A key
therapeutic objective in efforts to shift the immunologic balance towards tolerance, therefore, is to selectively
inhibit Teff and promote Treg. We have shown that Th17 and Treg cells utilize fundamentally different metabolic
programs, with Th17 being reliant on glucose uptake and glycolysis while Treg are primarily reliant on
mitochondrial pathways. In our efforts to better understand the metabolic demands of each subset that could
be targeted to selectively modulate CD4 T cells in inflammatory diseases, we have found that cytokine and
inflammatory signals that drive Th17 and Treg differentiation each play distinct roles in control of T cell
metabolism. Further, these metabolic changes may influence T cell fate through modulation of reactive oxygen
species (ROS) and epigenetic modifications of gene expression. We showed that while Th17 require the
glucose transporter Glut1 and glycolysis, FoxP3 and the Treg-inducing cytokine TGFβ inhibit this pathway and
Treg can suppress independent of Glut1. Treg are metabolically flexible, however, and Toll-like receptors (TLR)
ligands can stimulate Treg to increase glycolysis but with reduced suppressive capacity and expression of
FoxP3. To identify additional metabolic pathways that may provide new immune modulatory targets, we
performed high-resolution non-targeted metabolomics and metabolic network analyses. These studies
identified glutaminolysis and one carbon metabolism as selectively enriched in Th17 relative to Treg. Here we
will test the roles of Glutaminase (GLS) in glutaminolysis and Methylenetetrahydrofolate dehydrogenase 2
(MTHFD2) in and one carbon metabolism in Th17 and Treg. Treg did not require GLS, but Treg differentiation
and stability were suppressed by MTHFD2. In contrast, we show that Th17 cells require both GLS, and
MTHFD2. While glycolysis, glutaminolysis, and one carbon metabolism are linked and each modulate both
ROS and epigenetic marks, mechanisms by which they affect Treg and Th17 cells, remain unknown. Our data
have led to the hypothesis that regulation of these metabolic pathways is essential for Treg and Th17 cells
through control of ROS and epigenetic methylation and that GLS or MTHFD2 will provide new immuno-
modulatory targets for inflammatory diseases. We will: (1) Determine how Treg glycolysis and MTHFD2 are
regulated by inflammatory cues to control Treg function and FoxP3 expression; (2) Test signals that regulate
Th17 metabolism and ROS and epigenetic modifications as mechanisms by which Th17 cells require GLS and
MTHFD2; (3) Establish the in vivo potential of GLS and MTHFD2 as therapeutic targets to enhance Treg and
suppress Th17 cells in inflammation. Th...

## Key facts

- **NIH application ID:** 10120671
- **Project number:** 5R01DK105550-09
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Jeffrey C Rathmell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,330
- **Award type:** 5
- **Project period:** 2015-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120671

## Citation

> US National Institutes of Health, RePORTER application 10120671, Exploiting metabolic vulnerabilities of CD4 T cell subsets to control inflammatory disease (5R01DK105550-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120671. Licensed CC0.

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