Mechanisms of endogenous antigen processing by the MHC class II pathway: studies with viral and cellular proteins

MHC II 类途径内源性抗原加工的机制：病毒和细胞蛋白的研究

• 批准号: G0801936/1
• 负责人: Graham Taylor
• 金额: $ 54.84万
• 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: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0801936%2F1
• 关键词: Mechanisms; endogenous; antigen; processing; MHC

The immune system?s T cells recognise short protein fragments of proteins (called epitopes) that are made by various processing pathways and then displayed on the surface of the body?s cells. If a cell is infected with a virus or is cancerous then epitopes from viral or cancer-specific cellular proteins are displayed. T cells specific for these epitopes can then destroy the affected cell. Vaccines and immunotherapies are being developed that aim to harness T cells to selectively destroy virus-infected or cancerous cells in this way. It therefore becomes important to understand the processing pathways how epitopes are made, since these control the supply and composition of the epitopes displayed on the cell surface. To study how epitopes are made from proteins found in different locations within cells I have used Epstein-Barr virus (EBV) as a model. I have made T cells specific for different types of EBV protein and used these to study processing. This virus is associated with several different cancers therefore the lessons learnt from this system have direct medical impact as well as teaching us more about the immune system in general. I have found that some proteins are transferred between cells before processing while others are processed within the cell itself even though these are all located in the same cellular compartment, the nucleus. Furthermore my work also suggests that proteins within the nucleus are unavailable for processing by an important internal processing pathway called macro-autophagy. Here I intend to continue working in the EBV system to learn more about the rules governing how proteins are processed within cells. I will then extend the work to study how cellular proteins expressed in cancer cells are processed and in turn recognised by T cells and how these processes differ from viral proteins. Finally, I will study a range of inherited fatal neurological conditions, including Huntington?s disease, caused by proteins that form toxic aggregates. These aggregates may be cleared by some of the processing pathways and I wish to establish whether the rules learned from the EBV system will apply here also, whether nuclear-localised aggregates, like EBNA1, evade processing by macro-autophagy and if an alternative pathway called chaperone mediated autophagy can compensate.

免疫系统？S T细胞识别蛋白质的短蛋白质片段(称为表位)，这些蛋白质片段由各种加工途径形成，然后显示在人体的表面--S细胞。如果细胞感染了病毒或患了癌症，那么病毒或癌症特异性细胞蛋白的表位就会显示出来。然后，针对这些表位的T细胞可以摧毁受影响的细胞。疫苗和免疫疗法正在开发中，旨在利用T细胞以这种方式选择性地摧毁病毒感染的细胞或癌细胞。因此，了解如何形成表位的加工路径变得很重要，因为这些加工路径控制着显示在细胞表面的表位的供应和组成。为了研究细胞内不同位置的蛋白质是如何形成表位的，我使用了EB病毒(EBV)作为模型。我已经制作了针对不同类型EBV蛋白的T细胞，并用它们来研究加工过程。这种病毒与几种不同的癌症有关，因此从这个系统中吸取的教训具有直接的医学影响，并从总体上教会了我们更多关于免疫系统的知识。我发现，一些蛋白质在加工前在细胞之间转移，而另一些蛋白质则在细胞内部加工，尽管这些蛋白质都位于同一个细胞隔间--细胞核。此外，我的工作还表明，细胞核内的蛋白质无法通过一种名为宏自噬的重要内部处理途径进行处理。在这里，我打算继续在EBV系统中工作，以了解更多关于蛋白质在细胞内如何处理的规则。然后，我将继续研究癌细胞中表达的细胞蛋白是如何被T细胞处理并识别的，以及这些过程与病毒蛋白有何不同。最后，我将研究一系列遗传性致命神经疾病，包括由形成有毒聚集体的蛋白质引起的亨廷顿？S病。这些聚集体可能会被一些加工途径清除，我想确定从EBV系统学到的规则是否也适用于这里，是否像EBNA1这样的核定位聚集体通过宏观自噬逃避加工，以及一种称为伴侣介导的自噬的替代途径是否可以弥补。