# Regulation of metabolic pathways in NKT cells

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $539,735

## Abstract

ABSTRACT
In conventional T cells, signaling pathways that control cellular metabolism have a crucial role in dictating the
outcome of T cell activation and their effector function. Resting CD4 and CD8 T cells use predominantly
oxidative metabolism but stimulation leads them to sharply increase glucose metabolism and adopt aerobic
glycolysis as a primary metabolic program. However, little is known about metabolic regulation and its role for
cellular functions of Natural Killer T (NKT) cells although recent studies indicate an important role of
metabolism in NKT cell differentiation. NKT cells are a heterogeneous population that shows a high degree of
phenotypic and functional specialization. When activated, unlike conventional T cells, NKT cells exhibit a fast
and robust effector function such as cytokine release or cytotoxicity. NKT cells can exert either an inflammatory
or a regulatory function depending on the tissue type such as liver or adipose tissue, respectively, that are a
site of metainflammation. Thus, the metabolic regulation in NKT cells likely plays an important role in immune
diseases. To understand how NKT cells regulate their metabolism to mediate an appropriate immune response
under a different environment, we measured parameters that associate with the metabolic capacity and
compared them with that of CD4 T cells. Our study revealed that NKT cells are very different from CD4 T cells
in many ways. NKT cells rely more on oxidative phosphorylation for their survival and repurposed Glc carbon is
used for optimal cytokine expression. In addition, NKT cells rely on glutamine (Gln) metabolism for proliferation
but not to express IFN-. Gln starved NKT cells seem to be inefficient to switch to glucose (Glc) metabolism,
which is similar to Gln-addicted cancer cells. Metabolomic data revealed that NKT cells have elevated
glutamine metabolites prior to stimulation further supporting an essential role of Gln metabolism. mTORC and
AMPK is known to increase and decrease Gln metabolism, respectively. In line with this, NKT cells are
sensitive to mTORC inhibition but AMPK deficiency results in hyperproliferation and increased cytokine
expression. Based on our data, we hypothesize that the proper regulation of Gln metabolism is critical for NKT
cells’ survival and function, which is controlled by the balance between mTORC and AMPK activity. To test the
hypothesis, we propose two specific aims. Aim 1 will investigate the mechanisms by which Gln controls NKT
cell proliferation and function, and Aim 2 will focus on the mTORC-AMPK axis to discern the regulation of Gln
metabolism in NKT cells. Metabolic status and regulation in NKT cells is virtually unexplored and, therefore,
investigating the regulation of the metabolic networks in NKT cells is highly innovative. Undoubtedly, the
proposed studies are significant given the fact that these studies will address a poorly understood area, and
the results will establish specific and selective metabolic d...

## Key facts

- **NIH application ID:** 10048010
- **Project number:** 1R01AI148289-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Cheong-Hee Chang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $539,735
- **Award type:** 1
- **Project period:** 2020-07-07 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048010

## Citation

> US National Institutes of Health, RePORTER application 10048010, Regulation of metabolic pathways in NKT cells (1R01AI148289-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10048010. Licensed CC0.

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