# Regulation of Follicular T cell Responses in the Lung by Ion Channels

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $472,654

## Abstract

Project Summary
The overall goal of this application is to understand how ion channels in T cells regulate immune responses to
pulmonary infection with influenza virus. Influenza is major health risk and affect millions of patients in the US
and worldwide. CD4 T cells play a critical role in supporting germinal center B cells to produce neutralizing
antibodies against influenza virus and to become memory B cells, which together provide immunity against
reinfection. The function of CD4 T cells is regulated by ion channels that mediate the influx of calcium and
other ions. The calcium release-activated calcium (CRAC) channel, which is formed by ORAI1 proteins in the
plasma membrane, is one of the best characterized channels in T cells. It mediates a specific and essential
form of calcium influx, store-operated Ca2+ entry (SOCE), so called because it is triggered by the release of
calcium from the endoplasmic reticulum. Ca2+ release activates stromal interaction molecule 1 (STIM1) and
STIM2 and results in the opening of ORAI1 CRAC channels. Mutations in ORAI1 or STIM1 genes in human
patients that abolish SOCE cause immunodeficiency with recurrent infections due to impaired T cell function
and production of pathogen-specific antibodies. This defect is mimicked by STIM1/STIM2 double-deficient
mice, whose CD4 T cells fail to develop into follicular T helper (TFH) cells and to help B cells mature into
germinal center B cells after viral infection. We found that mice lacking STIM1/STIM2 in T cells cannot produce
virus-specific antibodies upon infection with lymphocytic choriomeningitis virus (LCMV) or vaccination with
influenza virus. Important goals of this application are to understand whether CRAC channels in TFH cells
control pulmonary immune responses to infection with influenza and to characterize the molecular mechanisms
by which CRAC channels control the development and function of TFH cells in influenza. Besides the CRAC
channel, about 600 ion channels and transporters are expressed in mammals, but to date only a few are
established to contribute to T cell-mediated immune responses. We hypothesize that other ion channels
besides the CRAC channel play important roles in regulating TFH cell-dependent humoral immunity to
influenza. However, no studies have systematically addressed this question so far, which is a major gap in our
knowledge of T cell physiology and adaptive immunity. We will address this gap and systematically screen for
and characterize ion channels that regulate TFH cell-dependent humoral immune responses to influenza in
vivo. The long-term goal of our study is to identify ion channels and downstream molecules they regulate that
can be targeted therapeutically to enhance humoral immunity to influenza infection and vaccination. Since
many ion channels are plasma membrane proteins, they are accessible to small molecule inhibitors or
biologicals such as monoclonal antibodies to modulate their function and immune responses to influenz...

## Key facts

- **NIH application ID:** 9993202
- **Project number:** 5R01AI130143-04
- **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:** $472,654
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993202

## Citation

> US National Institutes of Health, RePORTER application 9993202, Regulation of Follicular T cell Responses in the Lung by Ion Channels (5R01AI130143-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9993202. Licensed CC0.

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