Probing novel modes of molecular recognition by the leukocyte immunoglobulin-like receptor family

该研究项目的重点是一组相关蛋白，即白细胞免疫球蛋白样受体（LIR）家族，它们在一系列不同的免疫细胞表面表达。这些受体被认为在调节免疫系统中发挥着重要作用，通过传递信号来帮助激活或灭活表达它们的细胞。这些细胞包括对抗体产生很重要的B细胞，可以杀死感染病毒的细胞的T细胞，以及可以杀死感染细胞或肿瘤细胞的自然杀伤细胞（NK）。此外，许多受体在称为树突状细胞（dc）的特殊细胞上表达，树突状细胞将来自感染生物体的外来分子呈现给T、B和NK细胞，并通过这样做激活它们来消灭入侵的病毒、细菌甚至肿瘤细胞。因此，了解LIR受体的功能非常重要，不仅有助于我们掌握免疫系统如何正常调节自身，而且还有助于设计基于使用特定免疫细胞（如T细胞或dc）的癌症或病毒感染的新疗法。更好地了解LIR功能也可以改善自身免疫性疾病的治疗策略。LIR受体向其所在的免疫细胞发送刺激或抑制信号的能力，关键取决于受体对另一个细胞表面目标分子的识别。因此，为了了解LIR受体的功能，我们需要了解它们识别的目标分子，它们如何识别它们，以及后果是什么。这项研究计划将使用一系列不同的技术来回答这些问题，这样做将大大增加我们对LIR受体功能的理解。该建议建立在Willcox博士之前在该领域的工作基础上，该工作包括分析一种名为lr -1的受体如何识别一种名为I类MHC的目标分子，这种分子参与将部分病毒衍生蛋白呈现给T细胞。这项工作导致了关于其他LIR受体识别目标分子的新想法。特别地，它表明一组LIR受体（1组LIR）识别类似于I类MHC的靶分子，而另一组（2组LIR）识别不同的靶分子。该提案中概述的工作将涉及一系列结合研究，以直接测试哪些目标分子被特征不明显的1组LIRs识别，并将包括CD1的工作，CD1是一种类似于I类MHC的分子，最近被Willcox博士的团队确定为1组受体LIR-2识别的目标分子。除了结合研究之外，将通过生成相关蛋白质的晶体并将其暴露在x射线下来分析第1组LIR识别事件的结构。此外，实验提出的目的是确定哪些分子被2组lir识别，包括LIR-5，一种在抑制T细胞和呈递DC细胞的功能中起重要作用的受体。这些实验建立在Willcox博士实验室最近的结果之上，该结果表明，LIR-5可以识别存在于活化T细胞表面的靶分子，并且还将检测这些受体的结构。总的来说，本提案中概述的实验将帮助我们了解研究较少的LIR受体的功能。在这样做的过程中，他们将大大增加我们对免疫反应如何被控制的理解，并可能导致改进治疗癌症、病毒感染和自身免疫性疾病的策略。

This research project focusses on a group of related proteins, the Leukocyte Immunglobulin-like Receptor (LIR) family, which are expressed on the surface of a range of different immune cells. These receptors are thought to play important roles in regulating the immune system, by transmitting signals that either help activate or inactivate cells on which they are expressed. These cells include B cells, which are important for antibody production, T cells, which can kill cells infected with viruses, and Natural Killer (NK) cells that can kill infected or tumour cells. Also, many of the receptors are expressed on specialsed cells called dendritic cells (DCs) that present foreign molecules derived from infecting organisms to T, B and NK cells, and by doing so activate them to eradicate invading viruses, bacteria, or even tumour cells. Therefore, understanding LIR receptor function is important, not only in helping us grasp how the immune system normally regulates itself, but also in the design of new therapies for cancer or viral infection based on the use of particular immune cells such as T cells or DCs. A better understanding of LIR function could also lead to improved strategies for the treatment of autoimmune disorders. The ability of LIR receptors to send stimulating or inhibiting signals to the immune cell on which they are present depends critically on the receptors recognising target molecules on the surface of another cell. Therefore, in order to understand how LIR receptors function, we need to understand what target molecules they recognise, how they recognise them, and what the consequences are. This research proposal will use a range of different techniques to answer these questions, and in doing so will significantly increase our understanding of LIR receptor function. The proposal builds on previous work by Dr Willcox in this area, which involved analysing how a receptor called LIR-1 recognises a target molecule called class I MHC that is involved in presenting parts of virus-derived proteins to T cells. This work led to new ideas about what target molecules other LIR receptors recognise. In particular it suggested that one group of LIR receptors (group 1 LIRs) recognise target molecules similar to class I MHC, while another group (group 2 LIRs) recognise different target molecules. The work outlined in this proposal will involve a series of binding studies to directly test what target molecules are recognised by poorly characterised group 1 LIRs, and will include work on CD1, a molecule similar to class I MHC that has recently been identified as a target molecule recognised by the group 1 receptor LIR-2 by Dr Willcox' group. In addition to binding studies, the structures of group 1 LIR recognition events will be analysed by generating crystals of the proteins involved and exposing them to x-rays. Also, the experiments proposed aim to identify what molecules are recognised by group 2 LIRs, including LIR-5, a receptor that plays an important role in dampening down the function of T cells and the presenting DC cells. These experiments build on recent results from Dr Willcox' laboratory suggesting that LIR-5 recognises a target molecule present on the surface of activated T cells, and will also involve examining the structures of such receptors. Collectively, the experiments outlined in this proposal will help us to understand the function of poorly studied LIR receptors. In doing so, they will significantly increase our understanding of how immune responses are controlled, and could potentially lead to improved strategies for the treatment of cancer, viral infection and autoimmune diseases.