# Targeting Tfh Cell Metabolic Regulation in SLE and SLE-Associated Atherosclerosis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $581,911

## Abstract

PROJECT SUMMARY
Systemic lupus erythematosus (SLE) is characterized by autoantibody production and immune complex
deposition and affects five to seven million individuals worldwide. Atherosclerosis and cardiovascular disease
are common causes of early mortality in SLE, but immune-mediated mechanisms leading to this and other
disease sequelae are not well understood. Therefore, demand is high to identify targeted strategies to
overcome the undesirable side-effects of overt immunosuppression. In this application, we propose that the
cellular metabolism of follicular helper T cells (Tfh), critical in promoting autoreactive B cell responses, may
provide novel SLE therapeutic targets. Conversely, regulatory T cells (Treg) may protect. Our group has
demonstrated that activated T cells increase glucose and glutamine consumption as they proliferate and
differentiate into specific functional subsets. Importantly, differentiation and biosynthesis following activation
requires a distinct metabolic program. To date, Tfh metabolism remains poorly understood, but our data
suggest that both glucose and glutamine are essential and that Tfh appear to have high rates of glutaminolysis
and are limited by rates of glucose uptake. It is now clear that these metabolic pathways regulate chromatin
accessibility and gene expression by providing substrates for epigenetic modifications. Our data suggest that
Glutaminase (GLS) and ATP-Citrate Lyase (ACLY), which regulate glutamine-dependent production of α-
ketoglutarate (αKG) and conversion of glucose-derived citrate to acetyl-CoA, respectively, regulate epigenetic
marks, gene expression and differentiation essential for Tfh function. These observations build on our previous
work demonstrating that GLS-inhibition led to reduced αKG and differential alterations to histone methylation
and chromatin accessibility in CD4 Th1 and Th17 cells. Importantly, both GLS and ACLY-deficient T cells failed
to generate or maintain Tfh in an in vivo model of chronic inflammation. We have also used a model for SLE-
accelerated atherosclerosis and shown that T cells in atherosclerosis have increased rates of
metabolism. Further, Treg had reduced function and Tfh frequencies were increased. The current proposal
will test the hypothesis that Tfh cells require glutamine and citrate metabolism to regulate epigenetic marks and
chromatin accessibility to allow gene expression for germinal centers and autoantibody production in SLE and
that targeting GLS or ACLY will disrupt epigenetic regulation of Tfh differentiation to treat disease. We will: (1)
Establish the role of GLS and ACLY in differentiation, epigenetic regulation and gene expression, and
metabolism of Tfh cells, and (2) Test inhibition of GLS or ACLY to decrease autoantibody production in murine
SLE and impair circulating Tfh from SLE patients, and (3) determine the effect of manipulating Tfh metabolism
on SLE-accelerated atherosclerosis. Our proposal to test the metabolic regulators of...

## Key facts

- **NIH application ID:** 10029497
- **Project number:** 1R01AI153167-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** AMY S MAJOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $581,911
- **Award type:** 1
- **Project period:** 2020-05-20 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029497

## Citation

> US National Institutes of Health, RePORTER application 10029497, Targeting Tfh Cell Metabolic Regulation in SLE and SLE-Associated Atherosclerosis (1R01AI153167-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10029497. Licensed CC0.

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