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T cells become licensed in the lung to enter the central nervous system

机译：T细胞在肺部获得许可进入中枢神经系统

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摘要

The blood-brain barrier (BBB) and the environment of the central nervous system (CNS) guard the nervous tissue from peripheral immune cells. In the autoimmune disease multiple sclerosis, myelin-reactive T-cell blasts are thought to transgress the BBBI>2 and create a pro-inflammatory environment in the CNS, thereby making possible a second autoimmune attack that starts from the leptomeningeal vessels and progresses into the parenchyma3'6. Using a Lewis rat model of experimental autoimmune encephalo-myelitis, we show here that contrary to the expectations of this concept, T-cell blasts do not efficiently enter the CNS and are not required to prepare the BBB for immune-cell recruitment. Instead, intravenously transferred T-cell blasts gain the capacity to enter the CNS after residing transiently within the lung tissues. Inside the lung tissues, they move along and within the airways to bronchus-associated lymphoid tissues and lung-draining mediastinal lymph nodes before they enter the blood circulation from where they reach the CNS. Effector T cells transferred directly into the airways showed a similar migratory pattern and retained their full pathogenicity. On their way the T cells fundamentally reprogrammed their gene-expression profile, characterized by downregulation of their activation program and upregulation of cellular locomotion molecules together with chemokine and adhesion receptors. The adhesion receptors include ninjurin 1, which participates in T-cell intravascular crawling on cerebral blood vessels. We detected that the lung constitutes a niche not only for activated T cells but also for resting myelin-reactive memory T cells. After local stimulation in the lung, these cells j strongly proliferate and, after assuming migratory properties, enter the CNS and induce paralytic disease. The lung could therefore contribute to the activation of potentially autoaggressive T cells and their transition to a migratory mode as a prerequisite to entering their target tissues and inducing autoimmune disease.%关于免疫细胞怎样进入脑中的问题，对于了解rn中枢神经系统(CNS)的生理和病理过程非常重rn要。这篇论文描述了允许疾病诱导性效应子T-rn细胞进入脑中的一个机制。在“实验性自体免rn疫脑脊髓炎”(EAE)的一个大鼠“过继转移”模rn型中，能致脑炎的T-细胞先是在肺部暂时驻rn留，之后在CNS中积累。在进入CNS的过程中，它们对其基因表达特征和功能特性重新进rn行编程，最终使其能够穿过“血一脑”屏障。rn肺部是与外部环境直接接触的，所以是与宿rn主防卫体系相关的免疫细胞的一个逻辑归宿rn地，也许还为自体免疫细胞的形成提供了一个rn小环境。
机译：血脑屏障（BBB）和中枢神经系统（CNS）的环境可以保护神经组织免受周围免疫细胞的侵害。在自身免疫性疾病多发性硬化症中，认为髓磷脂反应性T细胞胚细胞侵袭BBBI> 2并在CNS中形成促炎环境，从而使第二次自身免疫攻击可能从软脑膜血管开始，并逐渐发展为parenchyma3'6。使用实验性自身免疫性脑脊髓炎的Lewis大鼠模型，我们在这里表明，与该概念的预期相反，T细胞胚细胞不能有效进入CNS，也不需要为免疫细胞募集准备BBB。取而代之的是，静脉内转移的T细胞原始细胞在短暂停留在肺组织内后获得进入CNS的能力。在肺组织内部，它们沿着气道并在气道内移动到支气管相关的淋巴样组织和引流纵隔淋巴结的肺部，然后才从中枢神经系统进入血液循环。直接转移到气道的效应T细胞表现出相似的迁移模式，并保留了全部致病性。 T细胞从根本上重新编程了其基因表达谱，其特征在于其激活程序的下调以及细胞运动分子以及趋化因子和粘附受体的上调。粘附受体包括忍痛素1，其参与脑血管上的T细胞血管内爬行。我们检测到肺不仅对活化的T细胞而且对静息的髓磷脂反应性记忆T细胞都构成了利基。在肺中受到局部刺激后，这些细胞会强烈增殖，并具有迁移特性后进入CNS并诱发麻痹性疾病。因此，肺可能有助于潜在的自激性T细胞的活化和向迁移模式的转变，这是进入其靶组织并诱发自身免疫性疾病的先决条件。 （CNS）的生理和病理过程非常重rn要。本文描述了允许疾病的诱导性效应子T-rn细胞进入脑中的一个机制。在“实验性自体免rn疫脑脊髓炎”（EAE）的一个大鼠“过继转移”模rn型中，能致脑炎的T细胞先是在肺部暂时驻rn留，之后在CNS中积累。在进入CNS的过程中，其引起基因表达特征和功能特性重新进进rn行编程，最终能够实现跨越“血一脑”屏障。rn肺部是与外部环境直接接触的，所以是与宿rn主防卫体系相关的免疫细胞的一个逻辑归宿rn地，也许还为自体免疫细胞的形成提供了一个rn小环境。

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  • 来源
    《Nature》 |2012年第7413期|p.675-679A2|共6页
  • 作者

    Francesca Odoardi; Christopher Sie; Kristina Streyl; Vijay K. Ulaganathan; Christian Schlaeger; Dmitri Lodygin; Klaus Heckelsmiller; Wilfried Nietfeld; Joachim Ellwart; Wolfgang E. F. Klinkert; Claudio Lottaz; Mikhail Nosov; Volker Brinkmann; Rainer Spang; Hans Lehrach; Martin Vingron; Hartmut Wekerle; Cassandra Fluegel-Koch; Alexander Fluegel;

  • 作者单位

    Institute for Multiple Sclerosis Research,Department of Neuroimmunology,Gemeinnutzige Hertie-Stiftungand University Medical Centre Gottingen,37073 Gottingen,Germany;

    Institute for Multiple Sclerosis Research,Department of Neuroimmunology,Gemeinnutzige Hertie-Stiftungand University Medical Centre Gottingen,37073 Gottingen,Germany;

    Max Planck Institute for Neurobiology,82152 Martinsried,Germany;

    Max Planck Institute for Neurobiology,82152 Martinsried,Germany;

    Institute for Multiple Sclerosis Research,Department of Neuroimmunology,Gemeinnutzige Hertie-Stiftungand University Medical Centre Gottingen,37073 Gottingen,Germany;

    Institute for Multiple Sclerosis Research,Department of Neuroimmunology,Gemeinnutzige Hertie-Stiftungand University Medical Centre Gottingen,37073 Gottingen,Germany;

    Max Planck Institute for Neurobiology,82152 Martinsried,Germany;

    Max Planck Institute for Molecular Genetics,14195 Berlin,Germany;

    lnstitute of Molecular Immunology,Helmholtz Zentrum Munchen,81377 Munich,Germany;

    Max Planck Institute for Neurobiology,82152 Martinsried,Germany;

    Institute for Functional Genomics,University of Regensburg,93053 Regensburg,Germany;

    College of Medicine,Nursing and Health Sciences,Regenerative Medicine Institute,National Centre for Biomedical Engineering Science,National University of Ireland,County Galway,Ireland;

    Autoimmunity,Transplantation and Inflammation Novartis Institutes for BioMedical Research,4056 Basel,Switzerland;

    Institute for Functional Genomics,University of Regensburg,93053 Regensburg,Germany;

    Max Planck Institute for Molecular Genetics,14195 Berlin,Germany;

    Max Planck Institute for Molecular Genetics,14195 Berlin,Germany;

    Max Planck Institute for Neurobiology,82152 Martinsried,Germany;

    Institute for Anatomy II,Friedrich Alexander University,91054 Erlangen,Germany;

    Institute for Multiple Sclerosis Research,Department of Neuroimmunology,Gemeinnutzige Hertie-Stiftungand University Medical Centre Gottingen,37073 Gottingen,Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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