# Investigating the role of L-2-hydroxyglutarate in helper T cell differentiation and function

> **NIH NIH F31** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $48,974

## Abstract

PROJECT SUMMARY/ABSTRACT
T helper (Th) cell differentiation into specialized lineages is critical for effective immune responses against
pathogens, but dysregulated Th differentiation can contribute to autoimmune diseases. Emerging evidence
suggests that metabolism can influence Th cell development and function, but which metabolites and metabolic
pathways are involved remains poorly understood. Somatic mutations in the isocitrate dehydrogenase (IDH)
enzymes contribute to the pathogenesis of acute myeloid leukemia (AML) and other malignancies via production
of the ‘oncometabolite’ D-2-hydroxyglutarate (D-2HG). D-2HG blocks differentiation of malignant cells by
inhibiting alpha-ketoglutarate (⍺KG)-dependent enzymes that regulate chromatin structure and gene expression.
Recent reports suggest that D-2HG can influence the balance of Th17 and Treg differentiation, but the findings
are contradictory and inconclusive. Whether CD4+ cells lacking IDH mutations produce physiologically relevant
levels of D-2HG remains unclear. This raises the question as to whether analogous metabolic pathways might
influence physiologic Th cell differentiation. Intriguingly, 2HG is a chiral molecule that can exist in either the D-
or L- enantiomer. Although cancer-associated IDH mutants exclusively produce D-2HG, our lab and others have
shown that virtually all normal and malignant cells produce L-2HG in response to hypoxia. Hypoxia-induced L-
2HG potently inhibits ⍺KG-dependent enzymes, including chromatin modifiers and regulators of hypoxia-
inducible factor (HIF) stability. Nonetheless, physiologic sources and functions of L-2HG remain poorly
understood. I discovered that activated Th cells produce L-2HG and that L-2HG levels are enhanced by hypoxia
and hydrogen sulfide (H2S), microenvironmental factors that are prominent within the intestine. Furthermore, I
found that genetic manipulations to elevate endogenous L-2HG in Th cells can promote T helper 17 (Th17) and
impair regulatory T cell (Treg) differentiation. Thus, I hypothesize that CD4+ helper T cells produce L-2HG in
response to specific microenvironmental cues to fine-tune the balance of Th17 and Treg cells and
enhance inflammatory responses. I will rigorously test this hypothesis in two Specific Aims. Aim 1 will dissect
the molecular mechanisms by which L-2HG regulates the balance of Th17 and Treg cells in vitro. In this aim, I
will use novel genetically engineered mouse models (GEMM) that allow for tissue-specific manipulation of
endogenous L-2HG levels to determine the effects of L-2HG on metabolism, chromatin structure, and gene
expression. Aim 2 will elucidate how both T cell-intrinsic and microenvironmental L-2HG regulate CD4+ T cell-
mediated inflammatory immune responses in vivo. Here, I will use novel GEMM to elevate and deplete L-2HG
in Th cells or intestinal epithelial cells in models of intestinal bacterial infection and autoimmune colitis. The
proposed studies will provide important insights in the ...

## Key facts

- **NIH application ID:** 10998452
- **Project number:** 1F31AI181502-01A1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Thomas Francis McNamara
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-08-05 → 2026-08-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998452

## Citation

> US National Institutes of Health, RePORTER application 10998452, Investigating the role of L-2-hydroxyglutarate in helper T cell differentiation and function (1F31AI181502-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10998452. Licensed CC0.

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