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

探索白细胞免疫球蛋白样受体家族分子识别的新模式

• 批准号: BB/E009417/1
• 负责人: Benjamin Willcox
• 金额: $ 55.89万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE009417%2F1
• 关键词: Probing; novel; modes; molecular; recognition

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.

该研究项目的重点是一组相关的蛋白质，白细胞免疫球蛋白样受体（LIR）家族，它们在一系列不同免疫细胞的表面上表达。这些受体被认为在调节免疫系统中发挥重要作用，通过传递信号来帮助激活或抑制表达它们的细胞。这些细胞包括对抗体产生很重要的B细胞、可以杀死被病毒感染的细胞的T细胞和可以杀死被感染细胞或肿瘤细胞的自然杀伤（NK）细胞。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源分子呈递给T、B和NK细胞，并通过这样做激活它们以根除入侵的病毒、细菌甚至肿瘤细胞。因此，了解LIR受体功能非常重要，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功能也可以改进治疗自身免疫性疾病的策略。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识别另一细胞表面上的靶分子。因此，为了了解LIR受体如何发挥作用，我们需要了解它们识别哪些靶分子，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。该提案建立在威尔考克斯博士在这一领域的先前工作基础上，该工作涉及分析一种名为LIR-1的受体如何识别一种名为I类MHC的靶分子，该分子参与将部分病毒衍生蛋白呈递给T细胞。这项工作导致了关于其他LIR受体识别的靶分子的新想法。特别地，它表明一组LIR受体（组1 LIR）识别与I类MHC类似的靶分子，而另一组（组2 LIR）识别不同的靶分子。本提案中概述的工作将涉及一系列结合研究，以直接测试哪些靶分子被特征不佳的1组LIR识别，并将包括CD 1的工作，CD 1是一种类似于I类MHC的分子，最近被威尔考克斯博士的小组确定为1组受体LIR-2识别的靶分子。除了结合研究，第1组LIR识别事件的结构将通过产生所涉及的蛋白质晶体并将其暴露于X射线来分析。此外，提出的实验旨在确定第2组LIR识别哪些分子，包括LIR-5，这是一种在抑制T细胞和呈递DC细胞功能方面发挥重要作用的受体。这些实验建立在威尔考克斯博士实验室的最新结果之上，该结果表明LIR-5识别存在于活化T细胞表面的靶分子，并且还将涉及检查此类受体的结构。总的来说，本提案中概述的实验将帮助我们了解研究不足的LIR受体的功能。通过这样做，它们将显著增加我们对免疫反应如何控制的理解，并可能导致改善癌症，病毒感染和自身免疫性疾病的治疗策略。

项目成果

Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self.

• DOI: 10.1038/ni.1660
• 发表时间: 2008-11
• 期刊: NATURE IMMUNOLOGY
• 影响因子: 30.5
• 作者: Mohammed, Fiyaz;Cobbold, Mark;Zarling, Angela L.;Salim, Mahboob;Barrett-Wilt, Gregory A.;Shabanowitz, Jeffrey;Hunt, Donald F.;Engelhard, Victor H.;Willcox, Benjamin E.
• 通讯作者: Willcox, Benjamin E.