Peptide antagonism and NK cell activation: mechanism and relevance

慢性病毒感染和癌症是疾病的主要原因，因此了解免疫系统如何识别细胞何时患病，以开发新的治疗方法非常重要。自然杀伤细胞在这种免疫反应中很重要。特别是，它们是免疫系统的一部分，是感染的第一道防线。它们还可以集结免疫系统的其他组成部分。最近的研究表明，不同的个体具有不同的控制自然杀伤细胞功能的杀伤细胞免疫球蛋白样受体（KIR）基因，这些基因差异导致对病毒和某些癌症的不同反应。特别是丙型肝炎病毒感染、HIV感染、流感感染、宫颈癌和肝癌的结果都可能取决于个体具有哪些KIR基因。到目前为止，人们还不清楚这些基因是如何工作的，以产生这些不同的疾病结果。然而，我们最近已经表明，由靶细胞表面上的MHC I类呈递的小肽（蛋白质片段）可以有效地诱导表达这些基因的NK细胞的活化。该项目的目的是通过详细研究自然杀伤细胞功能以及流感和丙型肝炎病毒对细胞的影响来解决这一问题，从而将其识别为患病细胞并与健康细胞区分开来。特别地，我们将研究来自病毒或自身蛋白的肽是否可以导致NK细胞识别感染的细胞。我们还将确定这种情况发生的速度，以及支持这种认识的机制。我们对自然杀伤细胞的了解越多，我们就越认识到它们对感染和癌症可能有许多不同和意想不到的作用。因此，它们可以参与对疫苗的反应，以及对慢性丙型肝炎病毒感染，艾滋病毒和癌症患者的免疫治疗的反应。因此，这项研究影响了我们对这些影响全世界数百万人的疾病的理解，并可能导致对抗这些疾病的新策略。

Chronic viral infections and cancer are major causes of disease, hence it is important to understand how the immune system recognizes when cells are diseased, in order to develop new treatments. Natural killer cells are important in this immune response. In particular they are part of the immune system that is the first line of defence to infections. They can also marshal other components of the immune system. Recent work has shown that different individuals have different killer cell immunoglobulin-like receptor (KIR) genes controlling the functions of natural killer cells, and that these genetic differences cause different responses to viruses and some cancers. In particular the outcomes of hepatitis C virus infection, HIV infection, influenza infection, cervical cancer and liver cancer may all depend on which KIR genes an individual has. To date it is not clearly understood how these genes work in order to generate these different outcomes of disease. However we have recently shown that small peptides (protein fragments) presented by MHC class I on the surface of target cells can efficiently induce activation of NK cells that express these genes. The aim of this project is to address this issue in a detailed study of both natural killer cell function and the effects of influenza and hepatitis C virus on cells leading to them being recognised as diseased and distinguishable from healthy cells. In particular we will study whether peptides derived from viral or self proteins can lead to recognition of infected cells by NK cells. We will also determine how quickly this may occur, and the mechanism that underpins this recognition. The more we understand about natural killer cells, the more we recognise that they can have many different and unexpected roles to infection and cancer. Hence they could participate in responses to vaccines, as well as to responses to immune therapies for individuals with chronic hepatitis C virus infection, HIV and also cancer. Thus the research impacts on our understanding of these diseases which affect many millions of people worldwide, and could lead to novel strategies to combat them.