# Regulation of T cell metabolism and function by IRGM proteins

> **NIH NIH R21** · DUKE UNIVERSITY · 2020 · $241,500

## Abstract

ABSTRACT
The Immunity-Related GTPases (IRG) are a family of genes that are induced by interferon gamma and/or LPS
and play pivotal roles in immune responses. Human IRGM gene variants are associated with increased risk of
Crohn’s Disease (CD) and other inflammatory diseases. Mice lacking an IRGM orthologue, Irgm1, exhibit a
similar spectrum of inflammatory and immune disorders, including increased intestinal inflammation. Despite the
profound consequences of deficiencies in IRGM proteins, the basic mechanisms through which they function
remain unclear. Based on preliminary data, we hypothesize that deficiencies in IRGM proteins lead to metabolic
dysregulation of T cells, influencing both effector and regulatory T cell subsets, resulting in immune dysfunction
and inflammatory disease. The following aims will test this hypothesis: Aim 1. Define functional deficiencies
among T cell subsets lacking Irgm1 and determine the underlying mechanism including the role of
altered cellular metabolism. Comprehensive functional analyses of T cells from Irgm1-/- mice will be used to
determine differences in T cell development and functional output. The mechanism underlying any alterations
will be determined by first defining a metabolic signature among Irgm1-deficient T cell subsets, and then applying
genetic or pharmacologic interventions to mitigate metabolic changes and determine whether this normalizes T
cell dysfunction. In addition, we will use a conditional T-cell specific Irgm1-deficient mouse to determine if the
impact on T cell function/metabolism is cell-intrinsic. Lastly, the role of Irgm1-regulated autophagy in metabolic
alterations will be addressed through pharmacological approaches. Aim 2. Identify the role of Irgm1 in a
mouse model of T cell-mediated intestinal inflammation. To determine whether altered Teff and/or Treg cell
function, as a result of Irgm1-deficiency, alter the development of intestinal inflammation, a T cell transfer model
of colitis will be tested using T cells from WT and Irgm1-/- mice. Additionally, T cells lacking both Glut1 and Irgm1
will be used to test the role of increased glucose metabolism in Irgm1-dependent T cell dysfunction in the
intestinal inflammation model. Aim 3. Determine the impact of IRGM gene variants on T cell metabolism
and function in a human cohort. Human T cells from a large cohort of individuals genotyped for IRGM CD risk
variants will be used in T cell metabolic analyses and assessments of in vitro immune and inflammatory function.
Potential correlations between altered T cell metabolism and immune cell dysfunction will be investigated, as will
the impact of normalization of T cell metabolism on function. Collectively, these studies will validate a new
mechanistic paradigm through which deficiency in IRGM proteins leads to immune dysfunction and inflammation.
This work will be innovative by producing a conceptual shift in our understanding of how IRGM proteins function.
This can be translated into ide...

## Key facts

- **NIH application ID:** 9870868
- **Project number:** 5R21AI135398-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Nancie MacIver
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $241,500
- **Award type:** 5
- **Project period:** 2019-02-12 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870868

## Citation

> US National Institutes of Health, RePORTER application 9870868, Regulation of T cell metabolism and function by IRGM proteins (5R21AI135398-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9870868. Licensed CC0.

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