# CRAC Channel Deficiency in Immunity to Infection

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $541,293

## Abstract

Summary
The goal of our research is to understand how defects in calcium influx in cells of the immune system cause
immunodeficiency in patients with inherited mutations in genes regulating calcium influx. Since the same
patients also suffer from anemia caused by autoantibodies against red blood cells, a second goal of our
research is to understand how calcium influx maintains immunological self-tolerance and prevents
autoimmunity. Our central hypothesis is that CRAC channels, which mediate calcium influx across the cell
membrane, are required for the function of different cells in the innate and adaptive arms of the immune
system that provide immunity to infection and prevent autoimmunity. CRAC channels are the main source of
calcium influx in most immune cells. They are formed by the channel protein ORAI1 and are activated by
STIM1 and STIM2. We have identified the first patients with mutations in ORAI1 and STIM1 genes who suffer
from a disease we called CRAC channelopathy that is characterized by immunodeficiency, autoimmunity, and
several non-immunological defects. Because CRAC channelopathy is a rare disease and patient samples are
limited, we generated mice that lack CRAC channels in T cells. By investigating immune responses in these
mice and by validating key results in samples of patients with CRAC channelopathy, we have been able to
define a critical role of CRAC channels in T cell-mediated immune responses, in particular for cellular and
antibody-mediated immunity to infection and for limiting immune responses during chronic infection that would
otherwise cause harmful inflammation. However, we are still far from having a complete picture of how CRAC
channels regulate immunity to infection. Beyond T cells, CRAC channels may also regulate innate immune
responses mediated by dendritic cells and neutrophils. Studies so far have yielded conflicting data whether
CRAC channels are required for innate immune cell function, and their role for innate immunity to infection has
not been studied. Besides immunity to infection, CRAC channels are essential for immunological self-tolerance
by controlling the development of regulatory T cells, which suppress the function of other immune cells and
thereby prevent autoimmunity. CRAC channel-deficient patients have fewer Treg cells, potentially explaining
their autoimmunity. How CRAC channels control the function of Treg cells and prevent autoimmunity is not
understood. To address these questions, we propose the following three specific aims: (1) We will analyze
inherited defects in ORAI1 and STIM1 genes of patients to understand the role of CRAC channels for immune
function and the molecular regulation of CRAC channels. (2) We will determine if CRAC channels are required
for innate immune responses by dendritic cells and neutrophils to fight bacterial and fungal infections. (3) We
will determine how CRAC channels control regulatory T cell function and prevent autoimmunity, in particular
autoimmune hemol...

## Key facts

- **NIH application ID:** 10134195
- **Project number:** 5R01AI097302-09
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** STEFAN FESKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $541,293
- **Award type:** 5
- **Project period:** 2012-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134195

## Citation

> US National Institutes of Health, RePORTER application 10134195, CRAC Channel Deficiency in Immunity to Infection (5R01AI097302-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10134195. Licensed CC0.

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