T cell Signalling events in vivo during the induction of Immunity and Tolerance

肠道不断地暴露在病毒、细菌和寄生虫中，这些威胁到它的功能，我们必须保护自己。这是保护性免疫反应的作用，为了对抗感染，肠道中含有免疫系统的一部分。然而，我们吃的大部分食物也是外国的？对于我们的免疫系统来说，大量无害的细菌(共生体)也是如此，它们正常地生活在我们的肠道中，是生命所必需的。重要的是，我们不要试图对这些有用的物质进行保护性免疫反应，因为这可能会导致严重的肠道疾病，如乳糜泻和克罗恩-S病。事实上，免疫系统通常对这些材料没有反应(耐受性)，因为它已经进化出区分危险和无害材料的机制。重要的是要了解这种情况是如何发生的，这不仅是为了有更好的机会治疗肠道疾病，而且因为非常需要新的疫苗来对抗肠道感染。此外，通过利用免疫系统的这种能力来对摄入的物质产生耐受性，可能会治疗一些炎症性疾病，如糖尿病和类风湿性关节炎。已经有相当多的人知道了其中涉及的细胞过程，现在似乎很清楚，决定特定数量的T淋巴细胞(携带CD4标记的细胞)如何反应的信号在对危险物质和无害物质的反应细胞中可能有很大不同。因此，有可能以这些信号中的一些为靶点，故意打开或关闭肠道中的免疫反应。然而，这一领域的进展一直受到以下事实的限制，即直接识别那些有反应的CD4+T细胞是极其困难的。此外，对这些信号的研究通常需要将细胞从免疫系统中移除，并接受严酷的生化过程。我们现在已经开发出新的模型，可以使用高灵敏度的激光驱动显微镜技术来跟踪正常和突变的抗原特异性T淋巴细胞，并在完整的免疫系统中对其进行表征，该技术可以评估单个细胞中的此类信号。通过现场分析这些事件，我们希望能够准确地识别可能被证明在疾病治疗和疫苗开发中有用的分子。

The intestine is continually exposed to viruses, bacteria and parasites which threaten its function and against which we must defend ourselves. This is the role of the protective immune response and to combat infection, the intestine contains parts of the immune system. However, the majority of the food we eat is also ?foreign? to our immune system, as are the huge numbers of harmless bacteria (commensals) that live normally in our intestines and are essential for life. It is important that we do not attempt to make protective immune responses against these useful materials, as this can lead to severe intestinal disorders such as coeliac disease and Crohn?s disease. Indeed, the immune system normally becomes unresponsive (tolerant) to these materials as it has evolved mechanisms for distinguishing between dangerous and harmless materials. It is important to understand how this happens, not only to have a better chance of treating intestinal disease, but also because there is a great need for new vaccines to combat infections of the intestine. In addition, it may be possible to treat a number of inflammatory conditions such as diabetes and rheumatoid arthritis by exploiting this ability of immune system to become tolerant to ingested materials. A considerable amount is already known about the cellular processes involved and it now seems clear that the signals dictating how a particular population of T lymphocytes (those carrying the CD4 marker) responds may be very different in cells reacting to dangerous versus harmless materials. Thus, it may be possible to target some of these signals to deliberately switch on or off immune responses in the intestine. However, progress in this area has been limited by the fact that it is extremely difficult to identify directly those CD4+ T cells that respond. Moreover, study of the signals usually requires cells to be removed from the immune system and submitted to harsh biochemical processes. We have now developed new models that allow normal and mutant antigen specific T lymphocytes to be tracked and characterised in the intact immune system with highly sensitive laser-driven microscopy techniques that can assess such signals in individual cells. By analysing these events in situ, we hope to be able to identify precisely molecules that might prove useful in treatment of disease and in vaccine development.