Brain immune responses:Cellular & Molecular Mechanisms

描述(由申请人提供)：免疫突触是免疫细胞相互作用的最新表征的显微解剖结构。在CTL和感染或恶性星形胶质细胞之间建立免疫突触后，这些星形胶质细胞就会从大脑中消除。单个CTL靶细胞如何应对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对T细胞的攻击做出了积极的反应。我们的数据表明，靶向感染的星形胶质细胞从多极细胞转变为单极细胞，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。我们将测试这种主动的细胞重组是否会影响T细胞攻击的最终结果，例如，感染星形胶质细胞的死亡或存活。在这项应用中，我们将检验一种假设，即感染的星形胶质细胞和肿瘤胶质瘤细胞都以积极的方式对T细胞攻击做出反应，并且这种反应是由T细胞依赖的Rho-GTPase信号通路的激活诱导的。我们将研究星形胶质细胞在体内和体外对T细胞攻击的反应，并分析这些反应背后的分子信号通路。我们认为，了解感染和恶性星形胶质细胞响应T细胞攻击的细胞和分子机制将有助于更好地消除神经病毒感染和脑肿瘤，提高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的目标下探索胶质细胞在体内和体外对免疫攻击的反应的细胞和分子基础。特定目标1将测试免疫突触的形成导致受感染星形胶质细胞极化的假设，这依赖于Rho-GTPase途径的激活；特定目标2将测试抗病毒T细胞和受感染星形胶质细胞之间体内成熟免疫突触的CTL信号是否有效地导致受感染星形胶质细胞的死亡，或者星形胶质细胞是否能够抵抗这种攻击；以及特定目标3将测试抗肿瘤T细胞对胶质瘤细胞的作用是通过免疫突触形成介导的假设。公共卫生相关性：在体内，抗病毒CTL和病毒感染或恶性星形胶质细胞之间形成免疫突触，导致其细胞结构的重组。我们认为这种反应会影响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。我们认为，了解感染和恶性星形胶质细胞对T细胞攻击做出反应的细胞和分子机制将有助于更好地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，或者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.