# Mechanisms of gamma delta intraepithelial lymphocyte-mediated host defense

> **NIH NIH F30** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $42,120

## Abstract

PROJECT SUMMARY/ABSTRACT.
The intestinal epithelium is the first line of defense against the trillions of bacteria in the intestinal lumen.
Failure to prevent or limit bacterial invasion can lead to infection and may trigger a harmful inflammatory
response, as seen in inflammatory bowel disease. Intraepithelial lymphocytes (IEL) expressing the γδ T cell
receptor rapidly respond to bacterial translocation through modulation of their migratory behavior and release
of soluble host defense factors, including cytokines and antimicrobial peptides (AMP). Though γδ IELs are an
essential part of host antibacterial response, many of the processes surrounding γδ IEL-mediated host defense
remain unclear. The objective of this application is to elucidate the mechanisms through which γδ IELs
contribute to host antibacterial defense. Preliminary data suggests that γδ IEL surveillance behavior and
effector function may be partially mediated by cell-autonomous recognition of microbe-associated molecular
patterns (MAMP) through Toll-like receptor/MyD88 signaling. Moreover, a newly-identified requirement for γδ
IELs in lipopolysaccharide (LPS)-induced epithelial cell shedding may represent a novel form of γδ IEL-
mediated host antibacterial defense, as extrusion of enterocytes infected with intracellular bacteria limits
pathogen proliferation within the epithelium. These observations have led to the central hypothesis that γδ
IELs contribute to host defense against bacterial invasion by activating migratory and effector responses
following cell-autonomous MAMP recognition and by promoting the shedding of infected enterocytes. The
aims of this application are to 1) determine the contributions of γδ IEL MyD88 signaling to host defense
against acute bacterial invasion and 2) determine the mechanisms through which γδ IELs regulate cell
shedding in response to acute bacterial challenge. The role of γδ IEL MyD88 in mediating MAMP-induced
changes in γδ IEL migration and cytokine/AMP secretion will be assessed using inducible, γδ T-cell-specific
MyD88 knockout mice and a combination of in vitro and in vivo approaches. Further, the contribution of γδ IEL
MyD88 to antibacterial defense will be determined using Salmonella Typhimurium infections. Next, the
mechanisms by which γδ T cells promote LPS-induced epithelial cell shedding will be interrogated by
quantifying cell shedding in mice exhibiting altered γδ IEL migratory phenotypes or following γδ TCR inhibition.
The requirement for γδ IELs in shedding of Salmonella-infected enterocytes will be assessed at early infection
timepoints. Completion of these aims will provide novel insight into the mechanisms driving γδ IEL-mediated
antibacterial defense. The results of these studies will contribute towards the long-term goal of determining
the therapeutic potential of targeting γδ IEL effector functions as a means to prevent excessive inflammation by
promoting rapid clearance of infection. The proposed research and training plan...

## Key facts

- **NIH application ID:** 9976324
- **Project number:** 5F30DK121391-02
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Madeleine Hu
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $42,120
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976324

## Citation

> US National Institutes of Health, RePORTER application 9976324, Mechanisms of gamma delta intraepithelial lymphocyte-mediated host defense (5F30DK121391-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976324. Licensed CC0.

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