# CD39 in gamma delta intraepithelial lymphocyte function

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $664,163

## Abstract

PROJECT SUMMARY.
Under homeostatic conditions, there is a balance between pro- and anti-inflammatory responses in the
intestinal mucosa to provide a rapid response to pathogen while preventing aberrant tissue damage. In
inflammatory bowel disease (IBD), disruption of this balance can lead to harmful inflammation resulting in
disease initiation or relapse. gd intraepithelial lymphocytes (IEL) provide the first line of defense against luminal
microorganisms and exhibit immunoregulatory capacity through the expression of CD39, which contributes to
the hydrolysis of extracellular ATP to adenosine. We and others have reported that the total number of gd IELs,
and CD39 expression on these cells, is reduced both in IBD patients and in a mouse model of Crohn’s
disease-like ileitis; however, the regulation of CD39 and its influence on gd IEL effector function remains
unclear. We now show that the frequency of immunoregulatory CD39+ gd IELs is decreased a month prior to
the onset of Crohn’s disease-like ileitis and the microbiota contributes to gd IEL CD39 expression. Further, we
recently described a novel transmissible gd IEL hyperproliferative (gdHYP) phenotype, in which the presence of a
unique microbiota increased gd IEL number and surveillance behavior. Our preliminary data show that WT
mice exhibiting the gdHYP phenotype also exhibit increased CD39 expression that is accompanied by a shift
toward mitochondrial metabolism and reduced cytokine production. Therefore, we propose to interrogate the
mechanisms by which CD39 expression is regulated in gd IELs, elucidate the extent to which CD39 is coupled
to gd IEL bioenergetic capacity, and investigate the intersection between antibiotic treatment and gd IEL
functionality in pouchitis. To address these questions, we will use a combination of ex vivo IEL culture,
IEL/enteroid co-culture, single cell metabolomics assays, and unique gd T cell-specific mouse strains to dissect
the molecular mechanisms involved in the upregulation of CD39 and immunometabolism in response to the
microbiota. Moreover, we will leverage access to retrospective and prospective longitudinal biobank samples to
both translate findings from animal studies and investigate the potential link between antibiotic therapy and gd
IEL CD39 expression in the context of pouch inflammation. These studies will further our understanding of the
cellular and molecular mechanisms involved in amplifying gd IEL regulatory function to maintain mucosal
homeostasis with the ultimate goal of preventing disease relapse in IBD patients.

## Key facts

- **NIH application ID:** 10998591
- **Project number:** 1R01DK141146-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Karen Leigh Edelblum
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $664,163
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998591

## Citation

> US National Institutes of Health, RePORTER application 10998591, CD39 in gamma delta intraepithelial lymphocyte function (1R01DK141146-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10998591. Licensed CC0.

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