Peptide-Specific Natural Killer Cell Receptors in Health and Disease

免疫系统的细胞必须区分敌友。他们通过使用称为受体的细胞表面蛋白质机器来实现这一点，这些受体可以“看到”感染或癌症的迹象。当受体“看到”它们的目标时，免疫细胞就会开始行动，一些细胞会杀死目标细胞，并通过产生分子信息来提醒其他细胞注意危险部位。不同的免疫细胞使用不同的受体组合来检测它们的目标。开发治疗感染和癌症的新药需要了解免疫细胞及其受体如何检测它们的靶点。免疫系统用来检测其目标的一种机制被称为“HLA抗原呈递途径”。HLA蛋白是几乎所有细胞上发现的特殊分子，具有从细胞内捕获小片段（肽）并将其置于细胞表面的独特能力。在感染和癌症期间，这些肽具有与健康细胞上通常不存在的氨基酸序列不同的氨基酸序列，可以被免疫细胞使用其专门的受体“看到”。多年来，我们已经知道称为T细胞的免疫细胞非常擅长检测这些HLA呈递肽，并使用称为T细胞受体（TCR）的特殊肽检测受体。最近，我和其他人的研究表明，在不同的免疫细胞，自然杀伤（NK）细胞上表达的受体也检测到这些肽。然而，与TCR相反，对这些肽特异性自然杀伤细胞受体（PSNKR）知之甚少。该项目的目标是全面了解PSNKRs如何有助于免疫。自然杀伤（NK）细胞是具有杀死受感染细胞和肿瘤能力的特化免疫细胞。PSNKRs包括称为NKG 2C、NKp 44的受体和巨噬细胞免疫球蛋白样受体（KIR）家族的一些成员。该项目的第一个目标将是使用新的筛选技术来定义PSNKR。我有研究KIR的专业知识，最近开发了筛选来定义KIR的KIR肽特异性，而NKG 2C和NKp 44的特异性将通过合作来定义。来自这些筛选的数据将提供可以预测任何HLA呈递的肽是否将结合PSNKR的算法。由HLA蛋白呈递的肽被称为“免疫肽组”，并且这些肽的身份（氨基酸序列）在细胞类型和疾病状况之间不同。这些肽在不同疾病下的身份是未知的。通过合作，免疫肽将从涉及多种人类疾病的细胞中定义，包括HIV感染，癌症和先兆子痫（妊娠障碍）。然后测试这些肽的PSNKR结合，通过预测算法促进，然后测试它们激活NK细胞的能力。在鉴定功能性PSNKR配体之后，将部署操纵免疫肽组以增加PSNKR结合肽的频率的方法。其中一种方法将开发一种称为抗体-肽表位缀合物（APEC）的新技术。APEC可以将肽递送到HLA蛋白的细胞表面并激活T细胞，将它们重定向到肿瘤。我将开发针对PSNKRs的APEC，这是一种潜在的新药，可以将NK细胞重新导向靶细胞。NK细胞表达除PSNKR之外的许多不同受体。我的最终目标是研究NK细胞如何整合来自PSNKRs和其他激活受体的信号。在存在结合其他NK细胞受体的蛋白质的情况下，通过小心地给药HLA蛋白质来控制NK细胞活化。这将有助于模拟PSNKRs在不同疾病背景下如何响应靶细胞。这项研究计划将为一个知之甚少的受体家族及其在多种人类疾病中的作用提供分子见解，促进新型分子药物的开发。

Cells of the immune system must differentiate friend from foe. They achieve this by using cell surface protein machines called receptors that can 'see' signs of infection or cancers. When receptors 'see' their targets, immune cells spring into action, and some will kill the target cells and alert other cells to the site of danger by producing molecular messages. Different immune cells use different combinations of receptors to detect their targets. Developing new medicines to treat infections and cancer requires understanding how immune cells and their receptors detect their targets. One mechanism the immune system uses to detect their targets is called the 'HLA antigen presentation pathway'. HLA proteins are specialized molecules found on almost all cells that have the unique ability to capture small fragments (peptides) from inside the cell and place them on the cell surface. During infections and cancer, those peptides have different amino acid sequences to those not normally found on healthy cells can be 'seen' by immune cells using their specialized receptors. For many years, we've known that immune cells called T cells are very good at detecting these HLA presented peptides and use a special peptide detecting receptor called the T cell receptor (TCR). Recently, my research and others have shown that receptors expressed on a different immune cell, natural killer (NK) cells, also detect these peptides. However, in contrast to TCRs, very little is known about these peptide-specific natural killer cell receptors (PSNKR). The goal of this project is to develop a comprehensive understanding of how PSNKRs contribute to immunity. Natural killer (NK) cells are specialized immune cells with the capacity to kill infected cells and tumours. The PSNKRs include receptors called NKG2C, NKp44 and some members of the killer-cell immunoglobulin-like receptors (KIR) family. The first goal of the project will be to define PSNKR using novel screening technologies. I have expertise in studying KIR and recently developed screens to define KIR peptide-specificity of KIR, while the specificities of NKG2C and NKp44 will be defined through collaborations. The data from these screens will feed algorithms that can predict whether any HLA presented peptide will bind PSNKRs or not. The peptides presented by HLA proteins are called the 'immunopeptidome' and the identity (amino acid sequence) of these peptides differs between cells types and in disease conditions. The identity of these peptides under different diseases are unknown. Through collaborations, immunopeptidomes will be defined from cells implicated in multiple human diseases including HIV infection, cancer and pre-eclampsia (a disorder of pregnancy). These peptides will then be tested for PSNKR binding, facilitated by prediction algorithms, and then tested their ability to activate NK cells. After identifying functional PSNKR ligands, methods to manipulate immunopeptidomes to increase the frequency of PSNKR binding peptides will be deployed. One method will develop a new technology called Antibody-peptide epitope conjugates (APEC). APECs can deliver peptides to the cell surface of HLA proteins and activate T cells, redirecting them towards tumours. I will develop APECs to target PSNKRs, a potentially novel medicine that can redirect NK cells towards target cells. NK cells express many different receptors in addition to PSNKRs. My final goal will be to investigate how NK cells integrate signals from PSNKRs and other activating receptors. NK cell activation will be controlled by carefully dosing HLA proteins in the presence of proteins that bind other NK cell receptors. This will help model how PSNKRs respond to target cells in different disease contexts. Together this research program will provide molecular insight into a poorly understood receptor family and their role in multiple human diseases, facilitating development of novel molecular medicines.