Membrane TNF and lymphotoxin control of chemokine induction and inflammation in tuberculosis

结核病（TB）仍然是世界范围内的一个巨大问题。大多数结核病不是由于感染时的疾病，而是在从未完全根除生物体的人中休眠疾病的重新激活。含有休眠结核菌的巨噬细胞位于称为肉芽肿的病变中。肉芽肿由TB感染的巨噬细胞组成，巨噬细胞被T淋巴细胞包围，T淋巴细胞积极控制感染。T淋巴细胞阻止结核菌在巨噬细胞中的生长，从而防止引起宿主疾病的广泛感染。识别TB感染的巨噬细胞的活化的T淋巴细胞在血液中循环，从毛细血管募集到肺中，通过组织迁移并与感染的巨噬细胞共定位。已知可溶性分子（细胞因子和趋化因子）提供指导细胞迁移和活化事件的信号。这项研究将详细调查所涉及的细胞因子和趋化因子，产生这些细胞的细胞以及这些细胞在肺中的位置。我们最近发现，肿瘤坏死因子（TNF）和相关的细胞因子趋化因子（LT）是淋巴细胞通过肺迁移所必需的。它们属于一个相关分子家族，通过同一组受体发出信号并调节趋化因子表达和炎症。在这项研究中，我们将使用缺乏TNF的基因操纵小鼠。LT或其他家族成员或仅表达膜结合TNF的细胞，以研究每种细胞如何影响不同趋化因子、趋化因子受体和其他分子的产生。由于已知的趋化因子至少有50种，趋化因子受体有17种，我们将利用微阵列技术同时筛选数千个基因表达的变化，并利用激光显微切割技术研究感染肺中不同部位的细胞。了解引导T细胞进入肉芽肿所必需的信号可能有助于预防结核病再活化疾病的新治疗。

Tuberculosis (TB) remains an enormous problem worldwide. Most TB is not due to disease at the time of infection, but is a reactivation of dormant disease in people who have never completely eradicated the organisms. Macrophages containing dormant TB organisms are located in lesions called granulomas. Granulomas consist of TB-infected macrophages surrounded by T lymphocytes that actively contain the infection. T lymphocytes prevent the growth of TB organisms in the macrophages and so prevent widespread infection that would cause illness in the host. Activated T lymphocytes that recognise TB-infected macrophages circulate in blood, are recruited from blood capillaries into the lung, migrate through the tissue and co-localise with infected macrophages. Soluble molecules (cytokines and chemokines) are known to provide the signals that direct cell migration and activation events. This study will investigate in detail cytokines and chemokines that are involved, the cells that produce then and where these cells are located in the lung. We recently showed that tumour necrosis factor (TNF), and the related cytokine lymphotoxin (LT), are essential for lymphocyte migration through the lung. These belong to a family of related molecules that signal through the same panel of receptors and regulate chemokine expression and inflammation. In this study we will use genetically manipulated mice that lack TNF. LT or other family members or that express only membrane-bound TNF to study how each affects production of different chemokines, chemokine receptors and other molecules. Since there are at least 50 known chemokines and 17 chemokine receptors we will use microarray technology to simultaneously screen changes in expression of several thousand genes and laser microdissection to study cells from different location in infected lungs. Understanding signals necessary to direct T cells into granulomas may facilitate new treatments to prevent TB reactivation disease.