The molecular basis of a novel mechanism of antigen presentation: phosphoantigen-dependent activation of Vgamma9/Vdelta2 T cells by BTN3A molecules.

抗原呈递新机制的分子基础：BTN3A 分子对 Vgamma9/Vdelta2 T 细胞的磷酸抗原依赖性激活。

• 批准号: MR/M020290/1
• 负责人: John Trowsdale
• 金额: $ 40.07万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM020290%2F1
• 关键词: molecular; basis; novel; mechanism; antigen

A particular sub-set of lymphocytes, gammadelta T cells, are found in the circulation but their precise function and how they are controlled has been obscure. A key insight has been made linking activation of gammadelta T cells to a human protein called BTN3A1. The importance of circulating gammadelta T cells is highlighted by the observation that their frequency in the blood can increase from a few percent in most people to up to 30-40% of total lymphocytes in response to infection and cancer. Their function is to home in and kill infected and cancerous cells. Most of the time, cancer cells and those cells in the body which are infected, by for example pathogenic bacteria, can be identified and destroyed by this surveillance mechanism. However, life-threatening cancers and harmful infections do occur. We know that part of the reason for this is a result of the ability of diseased cells to escape detection by the immune system. The realization that cancers and pathogens can modulate the immune response to favour their own growth and replication is a major theme in immunological research. We believe that understanding in detail the mechanism of gammadelta T cell activation and the role played by BTN3A proteins, will help us to intervene in this dynamic between the immune system and harmful diseases. Another aspect of our study is the realization that inappropriate regulation of cells such as gammadelta T cells can lead to another class of diseases, collectively termed autoimmunity. In this case, the potent killing ability of the immune system is directed against cells of the body in the absence of any overt disease from external sources, such as infection. The immune system appears to be responding to confusing signals and attacks seemingly healthy cells inappropriately. Again, a clear understanding of the mechanism of gammadelta T cell activation may help us to intervene positively and perhaps block inappropriate activation signals, thereby suppressing autoimmune disease progression. The central aim of our proposed work is directed towards these goals.

在血液循环中发现了一种特殊的淋巴细胞亚群--Gammadelta T细胞，但它们的确切功能和如何控制一直不清楚。一个关键的洞察力已经将Gammadelta T细胞的激活与一种名为BTN3A1的人类蛋白质联系起来。血液中伽玛德尔塔T细胞的频率可以从大多数人的几个百分点增加到总淋巴细胞的30%-40%，以应对感染和癌症，这一观察结果突显了循环Gammadelta T细胞的重要性。它们的功能是滋养和杀死感染细胞和癌细胞。大多数情况下，癌细胞和体内那些被致病菌等感染的细胞可以通过这种监测机制来识别和摧毁。然而，威胁生命的癌症和有害感染确实会发生。我们知道，造成这种情况的部分原因是疾病细胞逃避免疫系统检测的能力。认识到癌症和病原体可以调节免疫反应，有利于自身的生长和复制，这是免疫学研究的一个主要主题。我们相信，详细了解Gammadelta T细胞激活的机制和BTN3A蛋白所起的作用，将有助于我们干预免疫系统与有害疾病之间的这种动态变化。我们研究的另一个方面是认识到对Gammadelta T细胞等细胞的不适当调节可能会导致另一类疾病，统称为自身免疫。在这种情况下，免疫系统的强大杀伤力是在没有任何外部来源的明显疾病(如感染)的情况下针对身体细胞的。免疫系统似乎对令人困惑的信号做出了反应，并不适当地攻击了看似健康的细胞。同样，清楚地了解Gammadelta T细胞激活的机制可能有助于我们进行积极的干预，或许还可以阻止不适当的激活信号，从而抑制自身免疫性疾病的进展。我们提议的工作的中心目标就是朝着这些目标前进。

项目成果

Regulation of Human ?d T Cells by BTN3A1 Protein Stability and ATP-Binding Cassette Transporters

BTN3A1 蛋白稳定性和 ATP 结合盒转运蛋白对人类 ?d T 细胞的调节

• DOI: 10.17863/cam.25130
• 发表时间: 2018
• 作者: Rhodes D