IMPC: Activation and effector functions of novel antiviral T cell populations in vivo

病毒感染是一个主要的健康威胁。因此，了解防御病毒的机制是一个重要的目标。在对人类受试者的研究中，我们发现了一组新的细胞，它们似乎对急性和慢性病毒感染有反应。所研究的细胞被描述为MAIT细胞(粘膜相关不变T细胞)-这是一种最近被描述的但在人类血液中含量丰富的细胞类型，并且是某些部位的主要T细胞，如在肝脏中。众所周知，它们对某些类型的细菌有反应，但我们发现，它们对患者的病毒感染很容易产生反应-研究的疾病包括丙型肝炎、流感和登革热。我们继续展示了其他病毒的激活，如艾滋病毒、巨细胞病毒和新型疫苗。到目前为止，这项研究已经提供了一种激活MAIT细胞的机制。这取决于免疫系统通过产生特定的化学信使或细胞因子来对病毒的存在做出反应。这其中的一个关键开关，似乎在大多数情况下是至关重要的，是细胞因子白介素18(IL-18)的产生。这(与第二个信号结合在一起)是MAIT细胞激活所必需的，MAIT细胞具有非常高水平的这种分子的受体(IL18RAP)，使它们对它非常敏感。一旦被激活，MAIT细胞就可以做一系列事情来保护身体免受病毒的攻击，包括释放更多的化学信使，如干扰素，它可以抑制病毒的生长，或者通过杀死被感染的细胞。最后，作为背景，我们将这些发现扩展到人体内其他相关的细胞类型。所有这些都以IL18RAP和一系列相关分子的高水平表达为特征-在人类中，特别是一个名为CD161的分子-这使得它们很容易被识别。这包括不同类型的T细胞(CD4+T细胞、CD8+T细胞、伽马-德尔塔T细胞)，它们似乎具有相同的特征-通过IL18对病毒做出反应并归巢到组织。因此，我们拥有一支由相关细胞类型组成的“团队”，它们很可能提供了抵御病毒和其他生物的第一道防线。这类人体研究的一个问题是，无法证明MAIT细胞的反应(或其他类型的细胞)是否对感染具有保护作用，以及这些细胞在体内是如何激活的。研究这一问题的一种方法是使用小鼠模型分析体内的反应。在这项研究中，我们将：1.分析小鼠中哪些细胞代表与人类相同的IL18RAP表达亚群-这将包括MAIT细胞，但也包括组织中的相关亚群。这可以用老鼠来完成，在老鼠身上，这些细胞被用基因标签进行荧光标记。2.通过这种方式，我们还将能够跟踪Il18RAP在体内自然或对病毒感染的反应中发展和扩展时的表达。我们的目标是使用病毒感染，这对人类健康很重要，我们已经有了一些人类数据。我们还可以测试这些细胞在活体中的功能需要在多大程度上需要IL18信号。我们幸运的是，存在一种经过改造的小鼠，它可以表达这样的遗传标签，我们可以用它来跟踪细胞并测试这一途径的重要性。我们有使用病毒模型的经验，最近与合作者的未发表数据表明，MAIT细胞在预防严重流感方面非常重要。我们的目标是建立这个模型，这样我们就可以继续测试在MAITs和相关细胞类型的功能中具有重要作用的其他途径，然后将其扩展到其他模型，包括一个新的病毒性肝炎模型。长远来说，我会(与合作者)申请项目及/或发展途径资助计划拨款，资助实验，以确定我们是否可以利用这些细胞及其信号系统的力量，以预防人类受到挑战性的感染。

Viral infections represent a major health threat. Thus, understanding the mechanisms involved in defence against viruses is an important goal. In studies of human subjects we have identified a new group of cells which appear to respond to acute and chronic virus infections. The cells studied are described as MAIT cells (Mucosal associated invariant T cells) - this a recently described but abundant cell type in human blood, and the dominant T cell at certain sites such as in the liver. They are known to respond to certain types of bacteria, but we found they could readily respond to viral infections in patients - the diseases studied include Hepatitis C, Influenza and Dengue. We have gone on to show activation by other viruses such as HIV, cytomegalovirus and also novel vaccines. The research to date has provided a mechanism by which MAIT cells can get activated. This depends on the immune system responding to the presence of the virus by making particular chemical messengers or cytokines. A key switch in this, which appears to be crucial in most cases, is the production of a cytokine Interleukin 18 (IL-18). This (in combination with a second signal) is necessary for MAIT cell activation and MAIT cells possess a very high level of a receptor for this molecule (IL18RAP), making them very sensitive to it. Once activated the MAIT cells can do a range of things to protect the body against viruses, including releasing more chemical messengers such as interferons, which can suppress virus growth, or by killing cells which are infected. Finally by way of background, we have extended these findings to other related cell types in the human body. These are all characterised by high level expression of IL18RAP and a set of related molecules - in humans notably one named CD161 - which makes them easily identifiable. This includes different types of T cells (CD4+ T cell, CD8+ T cell, gamma-delta T cell), which appear to have the same features - response to viruses via IL18 and homing to tissues. Thus we have a "team" of related cell types which likely provide a first line of defence against viruses, as well as other organisms. One problem with such human studies is that it is not possible to prove whether the MAIT cell response (or those of the other cell types) is protective against infection, and also how the cells are activated in the body. One way of studying this is to analyse the response in vivo using a mouse model. In this study we will: 1. Analyse which cells in the mouse represent the equivalent IL18RAP expressing subsets to those seen in humans -this will include MAIT cells but also related subsets in tissues. This can be done using a mouse where such cells are labelled fluorescently using a genetic tag. 2. This way we will also be able to track the expression of Il18RAP as they develop and expand in the body, either naturally or in response to virus infections. We will aim to use virus infections which are important for human health and where we already have some data in humans.3. We can also test to what extent IL18 signalling is needed for the function of these cells in vivo.We are fortunate that a mouse exists which has been engineered to express such a genetic tag and which we can use to track the cells and test the importance of this pathway. We have experience in use of viral models and have recent unpublished data with collaborators which show that MAIT cells are important in protection against sever Influenza. We aim to establish this model so we can go on to test other pathways which will be importance in function of MAITs and related cell types and then expand this to other models including a new model for viral hepatitis. In the long run I will (with collaborators) apply for project and/or Developmental Pathway Funding Scheme grants to fund experiments to establish if we can harness the power of these cells and their signalling system to protect against challenging infections in humans.