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

项目摘要 本申请的总体目标是了解T细胞中的离子通道如何调节免疫应答， 流感病毒肺部感染。流感是主要的健康风险，影响美国数百万患者 和世界各地。CD 4 T细胞在支持生殖中心B细胞产生中和性T细胞中起关键作用。 抗体，并成为记忆B细胞，它们一起提供免疫力， 再感染CD 4 T细胞的功能由离子通道调节，离子通道介导钙离子的流入， 其他离子钙释放激活的钙通道（CRAC），是由视网膜中的ORAI 1蛋白形成的。 质膜是T细胞中最具特征的通道之一。它调节了一个特定的和必要的 钙内流的一种形式，即钙库操纵的钙内流（SOCE），之所以这么叫是因为它是由释放 从内质网中获取钙。Ca 2+释放激活基质相互作用分子1（STIM 1）， STIM 2，并导致打开ORAI 1 CRAC通道。人的ORAI 1或STIM 1基因突变 废除SOCE的患者由于T细胞功能受损而导致免疫缺陷和复发性感染 和病原体特异性抗体的产生。该缺陷由STIM 1/STIM 2双缺陷模拟 小鼠，其CD 4 T细胞不能发育成滤泡性T辅助（TFH）细胞，也不能帮助B细胞成熟为 生殖中心B细胞。我们发现T细胞中缺乏STIM 1/STIM 2的小鼠不能产生 感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）或接种 流感病毒。本申请的重要目标是了解TFH细胞中的CRAC通道是否 控制肺部对流感感染的免疫反应，并描述其分子机制 CRAC通道通过其控制流感中TFH细胞的发育和功能。除了CRAC 在哺乳动物中，约有600种离子通道和转运蛋白表达，但迄今为止只有少数几种在哺乳动物中表达。 建立有助于T细胞介导的免疫应答。我们假设其他离子通道 此外，CRAC通道在调节TFH细胞依赖的体液免疫中起重要作用， 流感。然而，到目前为止，还没有研究系统地解决这个问题，这是我们研究的一个主要空白。 了解T细胞生理学和适应性免疫。我们将解决这一差距，并系统地筛选 并表征了调节TFH细胞依赖的对流感的体液免疫应答的离子通道， vivo.我们研究的长期目标是确定离子通道和它们调节的下游分子， 可以在治疗上靶向增强对流感感染和疫苗接种的体液免疫。以来 许多离子通道是质膜蛋白，它们可被小分子抑制剂或 生物制剂如单克隆抗体来调节它们的功能和对流感的免疫应答。

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.