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

离子通道对肺滤泡 T 细胞反应的调节

基本信息

批准号：
9444252
负责人：
STEFAN FESKE
金额：
$ 50.55万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9444252
关键词：
ATAC-seq Address Affect Antibodies Antibody Formation Antiviral Agents Attenuated B-Lymphocytes Binding Biological Biological Response Modifiers CD4 Positive T Lymphocytes CRISPR/Cas technology Calcium Calcium Channel Cell Differentiation process Cell membrane Cell physiology Cells Cellular Immunity Cessation of life ChIP-seq Chromatin Custom Data Defect Development Endoplasmic Reticulum Event Gene Deletion Gene Expression Generations Genes Genetic Transcription Goals Health Helper-Inducer T-Lymphocyte Human Humoral Immunities Immune response Immunity Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunologic Deficiency Syndromes Impairment Incidence Infection Influenza Influenza A virus Influenza vaccination Ion Channel Ions Knowledge Libraries Life Lung Lymphocytic choriomeningitis virus Mammals Mature B-Lymphocyte Mediating Membrane Proteins Memory B-Lymphocyte Molecular Monoclonal Antibodies Mus Mutation Nature Pathway interactions Patients Plasma Cells Play Primary Infection Production Proteins Recurrence Regulation Risk Role STIM1 gene Severities Shapes Structure of germinal center of lymph node T cell response T-Cell Receptor T-Lymphocyte Testing Therapeutic Vaccinated Vaccination Virus Virus Diseases adaptive immunity antiviral immunity cell mediated immune response in vivo influenzavirus insight neutralizing antibody next generation sequencing novel pathogen response screening small hairpin RNA small molecule inhibitor targeted treatment transcription factor transcriptome sequencing whole genome

项目摘要

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 influenza.

项目概要该应用的总体目标是了解 T 细胞中的离子通道如何调节免疫反应流感病毒肺部感染。流感是主要的健康风险，影响着美国数百万患者以及全世界。 CD4 T 细胞在支持生发中心 B 细胞产生中和作用方面发挥着关键作用流感病毒抗体并成为记忆 B 细胞，共同提供针对流感病毒的免疫力再次感染。 CD4 T 细胞的功能受介导钙和离子流入的离子通道的调节。其他离子。钙释放激活钙 (CRAC) 通道，由 ORAI1 蛋白形成质膜是 T 细胞中特征最清楚的通道之一。它介导了特定且重要的钙离子内流的一种形式，即储存操作的 Ca2+ 进入 (SOCE)，之所以如此命名，是因为它是由钙离子的释放触发的。来自内质网的钙。 Ca2+ 释放激活基质相互作用分子 1 (STIM1) 并 STIM2 并导致 ORAI1 CRAC 通道打开。人类 ORAI1 或 STIM1 基因突变废除 SOCE 的患者会因 T 细胞功能受损而导致免疫缺陷并反复感染和病原体特异性抗体的产生。 STIM1/STIM2 双缺陷模仿了这种缺陷小鼠的 CD4 T 细胞无法发育为滤泡 T 辅助细胞 (TFH)，也无法帮助 B 细胞成熟为病毒感染后的生发中心B细胞。我们发现T细胞中缺乏STIM1/STIM2的小鼠不能产生感染淋巴细胞脉络膜脑膜炎病毒 (LCMV) 或接种疫苗后产生病毒特异性抗体流感病毒。该应用的重要目标是了解 TFH 细胞中的 CRAC 通道是否存在控制对流感感染的肺部免疫反应并表征其分子机制 CRAC通道通过该通道控制流感中TFH细胞的发育和功能。除了机房空调通道，大约 600 个离子通道和转运蛋白在哺乳动物中表达，但迄今为止只有少数旨在促进 T 细胞介导的免疫反应。我们假设其他离子通道此外，CRAC 通道在调节 TFH 细胞依赖性体液免疫中发挥重要作用流感。然而，迄今为止，还没有研究系统地解决这个问题，这是我们的一个重大差距。 T 细胞生理学和适应性免疫的知识。我们将解决这一差距并系统地筛选并表征了调节 TFH 细胞依赖性流感体液免疫反应的离子通道体内。我们研究的长期目标是确定离子通道及其调节的下游分子可以进行靶向治疗，以增强对流感感染和疫苗接种的体液免疫。自从许多离子通道是质膜蛋白，它们可被小分子抑制剂或生物制品，例如单克隆抗体，可调节其功能和对流感的免疫反应。