# Interferon regulation of gamma delta intraepithelial lymphocyte activation

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $352,631

## Abstract

PROJECT SUMMARY.
Immune surveillance at mucosal barriers is essential to provide an immediate defense against invasive
microbes, yet must also be tightly regulated limit the potential for autoimmunity. Intraepithelial lymphocytes
expressing the γδ T cell receptor (γδ IEL) bridge innate and adaptive immunity, and function as a first line of
defense by promoting mucosal barrier integrity. Recent reports demonstrate that basal γδ IEL function is
influenced by extrinsic microbial signals. Although commensal-induced tonic type I interferon (IFN) signaling
has been shown to prime mucosal innate immunity and host responsiveness to pathogen, the involvement of
type I IFN in γδ IEL activation and epithelial surveillance remains unknown. Our preliminary data demonstrate
that constitutive low level type I IFN signaling regulates the appropriate number and proportion of Vγ TCR
subsets in the epithelial compartment and maintain these cells in an actively patrolling, yet immunologically
quiescent state. We now show that impaired interferon α/β receptor (IFNAR) activation induces a dysregulated
γδ IEL phenotype, characterized by hyperproliferation, hypermotility and enhanced IL-4 expression. Further, we
find that pathogen-associated levels of type I IFN amplify γδ IEL effector functions, including epithelial
surveillance. Therefore, we propose to interrogate the mechanism by which tonic type I IFN signaling maintains
γδ IEL homeostasis, whereas amplification of type I IFN in response to pathogen enhances γδ IEL effector
function. In the first aim, we will take advantage of genetic models that permit the inducible γδ T-cell-specific
deletion of IFNAR to examine the role of tonic IFNAR/STAT signaling in the maintaining γδ IEL homeostasis
through appropriate regulation of different Vγ subsets. We will also investigate the mechanisms by which
IFNAR signaling regulates crosstalk between different γδ IEL subsets and how this influences the proliferation,
motility and effector function of these cells. Next, we will determine the functional consequence of γδ IEL
dysregulation on epithelial barrier integrity under steady-state conditions. In the second aim, we will examine
the mechanisms by which type I IFN amplifies γδ IEL effector function following viral infection. Using the novel
intravital microscopy techniques that we pioneered and our ability to move fluidly between in vitro and in vivo
models, we will investigate the molecular signals induced by pathogen-associated levels of type I IFN to
enhance γδ IEL epithelial surveillance and activation. Lastly, based on the protection conferred by γδ IELs in
response to enteric pathogens, we will examine the role of type I IFN-induced γδ IEL activation in the context of
acute enteric viral infection. By combining, temporal and cell-specific gene targeting, cutting edge live imaging
techniques, and novel models to analyze γδ IEL function ex vivo, we expect to define the molecular
mechanisms by which type I IFN regulates γδ ...

## Key facts

- **NIH application ID:** 9942412
- **Project number:** 5R01DK119349-02
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Karen Leigh Edelblum
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,631
- **Award type:** 5
- **Project period:** 2019-06-04 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942412

## Citation

> US National Institutes of Health, RePORTER application 9942412, Interferon regulation of gamma delta intraepithelial lymphocyte activation (5R01DK119349-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9942412. Licensed CC0.

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