# Regulation of pathogenic T cells in EAE

> **NIH NIH R01** · BENAROYA RESEARCH INST AT VIRGINIA MASON · 2020 · $428,750

## Abstract

Project Summary/Abstract
 Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation and
demyelination of the central nervous system (CNS). This results in progressive neurological dysfunction and
physical impairment. Auto-reactive CD4+ T cells play an important role in the initiation and progression of MS
and its mouse model (experimental autoimmune encephalomyelitis, EAE). T cell producing IL-17, IFN-g and GM-
CSF (Th17, Th1 and ThGM-CSF) have all been shown to play an important role in the immunopathogenicity of
MS and EAE. Although, there are currently
several disease modifying therapies (DMT), which reduce MS
symptoms, there is not yet a cure for this disease.
 Signal transducers and activators of transcription (STAT1) is a potent regulator of gene expression in
response to type I, II and III interferon and IL-27 but also has profound effect on cell proliferation, growth and
migration. Therefore, elimination of STAT1 has the potential to limit the generation and/or of pathogenic T cells.
However, this possibility had never been formally investigated in the context of EAE with the appropriate tools.
Here, we show for the first time that STAT1 conditional deletion in T cells abrogates the development of EAE. T
cells from these mice can differentiate in Th1 and Th17 cells but fail to accumulate in the CNS and do not cause
EAE. Furthermore, T cells with a conditional deletion of STAT1 produce more IL-10 and have more regulatory T
cells.
 STAT1 deficient mice develop exacerbated EAE, highlighting a protective role of STAT1 mediated
signaling in EAE development. However, the cell type(s) and molecular pathways responsible for STAT1
protective effect in EAE have not been delineated. Using a selective deletion of STAT1 in microglia, we have
established that STAT1 signaling in microglia is protective.
 These novel data suggest that limitation of STAT1 signaling in T cells and sustain STAT1 signaling in
microglia could be exploited to limit the development and progression of CNS autoimmunity.
The hypothesis that will be tested here is that different key regulatory mechanisms downstream of STAT1 in
specific cell types can be exploited to limit the development of CNS autoimmunity. Specifically, we propose:
Aim 1. To investigate the underlying mechanism by which the absence of STAT1 limits all subsets of pathogenic
 T cells.
Aim 2. To study how STAT1 controls regulatory T cell activity.
Aim 3. To determine the mechanisms by which STAT1 limit innate cell functions and the development of EAE.

## Key facts

- **NIH application ID:** 9823847
- **Project number:** 5R01AI129548-04
- **Recipient organization:** BENAROYA RESEARCH INST AT VIRGINIA MASON
- **Principal Investigator:** Estelle Bettelli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $428,750
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9823847

## Citation

> US National Institutes of Health, RePORTER application 9823847, Regulation of pathogenic T cells in EAE (5R01AI129548-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9823847. Licensed CC0.

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