# Regulation of encephalitogenic T cells by CRAC channels

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $482,707

## Abstract

Project Summary
Multiple Sclerosis (MS) is an autoimmune disorder that is characterized by inflammation of the central nervous
system (CNS) and localized destruction of the brain and spinal cord resulting in debilitating neurological
symptoms. The disease processes underlying MS have been studied extensively in an animal model called
experimental autoimmune encephalomyelitis (EAE), which greatly helped to develop several approved
therapies for MS. In both MS and EAE, CD4+ helper T cells mistakenly recognize myelin protein expressed by
brain cells as foreign and mount an autoimmune response against it. This inflammatory response is mediated
mainly by two subsets of helper T cells, so-called Th1 and Th17 cells, which infiltrate the CNS and produce the
proinflammatory cytokines IFNγ and IL-17, respectively. Interfering with the development of naive CD4+ T cells
into Th1 and Th17 cells by genetic deletion of the transcription factors T-bet and RORγt, respectively, protects
mice from EAE. Our lab showed that CD4+ T cells require the influx of calcium ions for their activation and
ability to produce IFNγ and IL-17. Calcium influx is mediated by CRAC (calcium release-activated calcium)
channels that are located in the plasma membrane of cells and formed by ORAI1 proteins. ORAI1 is activated
by two intracellular proteins, STIM1 and STIM2, and deletion or mutagenesis of either of these three proteins
attenuates CRAC channel function and calcium influx. Using mice with genetic deletion of ORAI1, STIM1 and
STIM2 as well as specific CRAC channel inhibitors, we found that Th1 and Th17 cells are more dependent on
calcium influx than other T cells for their function and ability to cause autoimmune inflammation. Treatment of T
cells of mice or humans with a specific CRAC channel inhibitor reduced the production of IL-17 and IFNγ but
did not affect T regulatory (Treg) cells. in a dose dependent manner. By genetically ablating either ORAI1,
STIM1 or STIM2 in T cells, we could prevent or ameliorate the development of EAE and CNS inflammation in
mice. Importantly, deletion of ORAI1 or STIM1 in T cells after EAE symptoms had already developed stopped
the progression of disease. Similarly, treatment of mice in which EAE had developed with a CRAC channel
inhibitor also significantly reduced disease severity without apparent adverse effects. These data suggest that
calcium influx is an essential mediator of CNS inflammation in EAE and that its inhibition may be a new option
for the treatment of MS. Drugs inhibiting CRAC channels have been developed, but have not been tested for
their efficacy and safety in the treatment of MS and other T cell mediated autoimmune diseases. The goals of
this application are twofold: (1) To understand the molecular mechanisms by which calcium influx via CRAC
channels controls the development of CD4 T cells into pathogenic T cells, in particular Th1 and Th17 cells, that
mediate CNS inflammation and EAE/MS. (2) To evaluate CRAC channels as d...

## Key facts

- **NIH application ID:** 9981624
- **Project number:** 5R01AI137004-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** STEFAN FESKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $482,707
- **Award type:** 5
- **Project period:** 2018-09-14 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981624

## Citation

> US National Institutes of Health, RePORTER application 9981624, Regulation of encephalitogenic T cells by CRAC channels (5R01AI137004-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9981624. Licensed CC0.

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