Brain immune responses:Cellular & Molecular Mechanisms

描述（由申请人提供）：免疫突触是最近表征的免疫细胞相互作用基础的显微解剖结构。CTL和感染或恶性星形胶质细胞之间免疫突触的建立先于这些星形胶质细胞从脑中消除。单个CTL靶细胞如何响应T细胞攻击仍然知之甚少。我们有证据表明，受感染的星形胶质细胞以积极的方式对T细胞的攻击作出反应。我们的数据表明，目标感染的星形胶质细胞从多极细胞变为单极细胞，即它们采用了一种新的极化表型，似乎包括细胞骨架和细胞内细胞器的重组。我们将测试这种活跃的细胞重组是否会影响T细胞攻击的最终结果，例如受感染星形胶质细胞的死亡或存活。在本申请中，我们将检验以下假设：受感染的星形胶质细胞和肿瘤神经胶质瘤细胞均以主动方式响应T细胞攻击，并且这种响应是由T细胞依赖性的Rho-GT3信号传导途径活化诱导的。我们将在体内和体外研究星形胶质细胞对T细胞攻击的反应，并分析这些反应背后的分子信号通路。我们相信，了解受感染和恶性星形胶质细胞对T细胞攻击的反应的细胞和分子机制，应该会导致更好的方法来消除神经病毒感染和脑肿瘤，增强基因治疗病毒载体的治疗性转基因表达，或保护大脑免受自身免疫攻击。为此，我们建议在三个特定目标中探索胶质细胞对体内和体外免疫攻击反应的细胞和分子基础。具体目标1将测试免疫突触的形成导致受感染的星形胶质细胞的极化并且这依赖于Rho-GT3途径的激活的假设;具体目标2将测试抗病毒T细胞和受感染的星形胶质细胞之间的体内成熟免疫突触处的CTL信号传导是否有效地导致受感染的星形胶质细胞的死亡，或者星形胶质细胞是否能够承受这种攻击;和特异性目标3将检验抗肿瘤T细胞对胶质瘤细胞的作用是通过免疫突触的形成介导的假设。公共卫生相关性：免疫突触在体内形成于抗病毒CTL和病毒感染或恶性星形胶质细胞之间，引起其细胞结构的重组。我们相信这种反应会影响T细胞攻击的最终结果，例如感染或肿瘤胶质细胞的死亡或存活。我们相信，了解受感染和恶性星形胶质细胞对T细胞攻击的反应的细胞和分子机制，应该会导致更好的方法来消除神经系统病毒感染和脑肿瘤，增强基因治疗病毒载体的治疗性转基因表达，或在自身免疫攻击的情况下保护大脑。

DESCRIPTION (provided by applicant): Immunological synapses are the recently characterized microanatomical structures that underlie immune cellular interactions. Establishment of immunological synapses between CTLs and infected or malignant astrocytes precedes the elimination of these astrocytes from the brain. How individual CTL target cells respond to T cell attack remains poorly understood. We have evidence suggesting that infected astrocytes respond in an active manner to the T cell attack. Our data suggests that target infected astrocytes change from multipolar to unipolar cells, i.e. they adopt a novel polarized phenotype that appears to include a reorganization of the cytoskeleton and intracellular organelles. We will test whether this active cellular reorganization could influence the ultimate outcome of the T cell attack, e.g. death or survival of infected astrocytes. In this application we will test the hypothesis that both infected astrocytes and tumor glioma cells respond in an active manner to T cell attack, and that this response is induced by a T cell-dependent activation of a Rho-GTPase signaling pathway. We will study the astrocyte responses to T cell attack in vivo and in vitro, and analyze the molecular signaling pathways underlying these responses. We believe that understanding the cellular and molecular mechanisms by which infected and malignant astrocytes respond to T cell attack should lead to better ways to eliminate neurological viral infections and brain tumors, enhance therapeutic transgene expression from gene therapy viral vectors, or protect the brain from autoimmune attack. To do so, we propose to explore the cellular and molecular basis of glial cell responses to immune attack both in vivo and in vitro in three Specific Aims. Specific Aim 1 will test the hypothesis that formation of immunological synapses leads to the polarization of infected astrocytes and that this is dependent on the activation of a Rho-GTPase pathway; Specific Aim 2 will test whether CTL signaling at mature immunological synapses in vivo between anti-viral T cells and infected astrocytes effectively leads to the death of infected astrocytes, or whether astrocytes can withstand such an attack; and Specific Aim 3 will test the hypothesis that the effects of anti- tumor T cells on glioma cells are mediated through the formation of immunological synapses. PUBLIC HEALTH RELEVANCE: Immunological synapses form in vivo between antiviral CTLs, and virally infected or malignant astrocytes causing a reorganization of their cellular structure. We believe this response influences the ultimate outcome of the T cell attack, e.g. death or survival of infected or tumor glial cells. We believe that understanding the cellular and molecular mechanisms by which infected and malignant astrocytes respond to T cell attack should lead to better ways of eliminating neurological viral infections and brain tumors, enhance therapeutic transgene expression from gene therapy viral vectors, or protect the brain in cases of autoimmune attack.