Peptide-Specific Natural Killer Cell Receptors in Health and Disease

免疫系统的细胞必须区分敌人和朋友。他们通过使用一种叫做受体的细胞表面蛋白质机器来实现这一目标，这种机器可以“看到”感染或癌症的迹象。当受体“看到”它们的目标时，免疫细胞就会行动起来，其中一些细胞会杀死目标细胞，并通过产生分子信息向其他细胞发出危险警报。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目标。免疫系统用来检测目标的一种机制被称为“HLA抗原递呈途径”。HLA蛋白是一种特殊的分子，几乎存在于所有细胞中，具有从细胞内部捕获小片段（肽）并将其放置在细胞表面的独特能力。在感染和癌症期间，这些肽与健康细胞中通常没有的肽具有不同的氨基酸序列，可以被免疫细胞利用其专门的受体“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呈现的肽，并使用一种特殊的肽检测受体，称为T细胞受体（TCR）。最近，我和其他人的研究表明，在不同的免疫细胞上表达的受体，自然杀伤（NK）细胞，也检测到这些肽。然而，与tcr相比，人们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如何促进免疫。自然杀伤细胞（NK）是一种特殊的免疫细胞，具有杀死受感染细胞和肿瘤的能力。PSNKRs包括被称为NKG2C、NKp44的受体和杀伤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是使用新的筛选技术来定义PSNKR。我在研究KIR方面有专业知识，最近开发了确定KIR肽特异性的筛选方法，而NKG2C和NKp44的特异性将通过合作来确定。来自这些筛选的数据将提供算法来预测HLA呈递的肽是否会与PSNKRs结合。HLA蛋白呈现的肽被称为“免疫肽穹窿”，这些肽的身份（氨基酸序列）因细胞类型和疾病状况而异。这些多肽在不同疾病下的特性尚不清楚。通过合作，免疫肽组将从涉及多种人类疾病的细胞中确定，包括艾滋病毒感染、癌症和先兆子痫（一种妊娠障碍）。然后，这些肽将通过预测算法进行PSNKR结合测试，然后测试它们激活NK细胞的能力。在确定功能性PSNKR配体后，将部署操作免疫肽的方法来增加PSNKR结合肽的频率。其中一种方法将开发一种称为抗体-肽表位偶联（APEC）的新技术。APECs可以将多肽传递到HLA蛋白的细胞表面，激活T细胞，使其转向肿瘤。我将开发APECs靶向PSNKRs，这是一种潜在的新药，可以将NK细胞定向到靶细胞。NK细胞除了表达PSNKRs外，还表达许多不同的受体。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。NK细胞的激活将通过在与其他NK细胞受体结合的蛋白存在的情况下小心地给药HLA蛋白来控制。这将有助于模拟PSNKRs在不同疾病背景下对靶细胞的反应。总之，这个研究项目将为一个鲜为人知的受体家族及其在多种人类疾病中的作用提供分子洞察力，促进新型分子药物的发展。

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.