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

免疫系统？T细胞识别蛋白质的短蛋白质片段（称为表位），这些蛋白质片段是通过各种加工途径产生的，然后显示在身体表面？年代的细胞。如果一个细胞被病毒感染或癌变，那么来自病毒或癌症特异性细胞蛋白的表位就会显示出来。这些表位特异的T细胞可以摧毁受影响的细胞。正在开发疫苗和免疫疗法，旨在利用T细胞以这种方式选择性地破坏病毒感染的细胞或癌细胞。因此，了解表位如何形成的加工途径变得很重要，因为这些途径控制着在细胞表面显示的表位的供应和组成。为了研究表位是如何由细胞内不同位置发现的蛋白质形成的，我使用了eb病毒（EBV）作为模型。我已经制造了针对不同类型EBV蛋白的特异性T细胞，并用它们来研究处理过程。这种病毒与几种不同的癌症有关，因此从该系统中吸取的经验教训具有直接的医学影响，同时也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间转移，而另一些则在细胞内加工，尽管它们都位于同一个细胞室，即细胞核。此外，我的工作还表明，细胞核内的蛋白质无法通过称为宏观自噬的重要内部加工途径进行加工。在这里，我打算继续在EBV系统中工作，以了解更多关于控制蛋白质在细胞内加工的规则。然后，我将扩展这项工作，研究癌细胞中表达的细胞蛋白是如何加工的，然后被T细胞识别，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系统疾病，包括亨廷顿舞蹈症？S疾病，由形成有毒聚集体的蛋白质引起。这些聚集体可能被一些加工途径清除，我希望确定从EBV系统中学习到的规则是否也适用于此，核局部聚集体，如EBNA1，是否通过宏观自噬逃避加工，以及是否有一种称为伴侣介导的自噬的替代途径可以补偿。

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.