# gd IELs in chronic ileitis

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $467,527

## Abstract

PROJECT SUMMARY.
Maintenance of an intact intestinal barrier is critical to prevent microbial activation of mucosal immunity. In
inflammatory bowel disease, this barrier is compromised, thus exposing the mucosal immune system to the
contents of the intestinal lumen. A substantial increase in the shedding or extrusion of epithelial cells into the
lumen has been shown to be a predictor of relapse in Crohn’s disease (CD) patients. gd intraepithelial
lymphocytes (IEL) migrate extensively within the epithelial compartment to serve as a first line of defense
against invasive microorganisms and facilitate apoptotic cell shedding. Although gd IELs are protective in
mouse models of colitis, the involvement of these sentinel lymphocytes in the pathogenesis of chronic ileitis is
less clear. Published reports provide conflicting evidence regarding the contribution of gd IELs in the
pathogenesis of chronic ileitis; however, we now show that inducible depletion of gd T cells prior to disease
initiation increases lethality. Further, detailed immunoprofiling of the IEL compartment in mice that develop
spontaneous CD-like ileitis indicates that the loss of gd IELs coincides with the histological onset of ileal
inflammation, suggesting that loss of gd IELs may be an initiating event. In support of this, we observe a
reduction in the frequency of CD39+ gd Tregs, while less activated, peripheral Vg1+ T cells infiltrate the IEL
compartment prior to disease development. Therefore, we propose to interrogate the contribution of gd IELs in
the pathogenesis of chronic ileitis and elucidate the cellular and molecular mechanisms involved in the
dysregulation of the gd IEL compartment during the development of CD-like ileitis. To address these questions,
we will take advantage of unique gd T-cell-specific mouse models and intravital microscopy to define how gd
IEL motility and effector function are regulated in the events leading up to the onset of chronic ileitis. By
combining temporal and cell-specific gene targeting, cutting-edge live imaging techniques, and novel models to
analyze gd IEL function ex vivo, we expect to clearly elucidate the contribution of gd IELs to the development of
ileal disease and further define the functional dysregulation within gd IEL subpopulations in the context of
chronic inflammation. Developing a better understanding of the cellular and molecular mechanisms involved in
gd IEL immunosurveillance and immunoregulation may elucidate additional targets for future therapies
designed to reinforce the epithelial barrier and prevent disease relapse.

## Key facts

- **NIH application ID:** 10877679
- **Project number:** 5R01DK135272-02
- **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:** $467,527
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877679

## Citation

> US National Institutes of Health, RePORTER application 10877679, gd IELs in chronic ileitis (5R01DK135272-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10877679. Licensed CC0.

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