Identifying mechanisms and determinants of T cell control over B cell fate choice in the germinal centre response.

免疫系统会对不同的独特目标做出相应的反应，这些目标被称为“抗原”，但人们并不清楚这是如何实现的。两种类型的免疫细胞——T细胞和B细胞——在识别免疫攻击的特异性方面发挥着同样重要的作用，它们都参与决定对特定抗原产生的免疫反应的类型和性质。在整个反应过程中，它们通过相互之间直接的身体互动来交换信号。这些信号对B细胞的活化及其产生的抗体的质量尤为重要。T细胞提供给B细胞的信号的性质，它们如何影响抗体反应的质量，以及重要的是，这是如何反过来受到目标抗原的影响的，这些都没有得到很好的理解。我们建议使用我们已经展示的工程抗原自然产生不同的免疫结果，作为一种实验方法来研究免疫系统如何产生不同的反应。我们最近发现了两种不同的抗原，它们产生非常不同的B细胞反应，并表明我们可以改变抗原的T细胞部分来影响B细胞的结果。在这个应用中，我们建议设计NPOVA抗原的变体，并使用它直接剖析应答B细胞之间的相互作用以及它们交换的不同信号以产生不同的免疫结果。在我们研究的第一个目标中，我们将使用先进的显微镜直接观察活组织中抗原特异性T细胞和B细胞之间的相互作用，因为它们对不同的工程NPOVA变体做出反应。我们的初步研究表明，相互作用的持续时间和相互作用细胞的膜纠缠的程度与B细胞反应的质量有关，这可以通过改变抗原的T细胞部分来控制。B细胞产生抗体，而T细胞和B细胞之间的相互作用被认为是提高所产生抗体质量的重要因素。在第二个AIM中，我们将确定是否可以通过我们的工程抗原变体影响抗体质量。在第三个AIM中，我们将识别被我们的工程抗原变异改变并导致不同B细胞结果的T细胞信号。目的是确定免疫系统如何控制对不同抗原的反应。这些研究对我们了解免疫系统的基本功能非常重要，也可能为未来疫苗的设计提供信息，以产生更有用的免疫反应。

The immune system tailors how it responds to different unique targets called "antigens", but it not well understood how this is achieved. Two types of immune cell - T cells and B cells - share the important role of identifying a specific for immune attack and both are involved in determining the type and nature of the immune response that develops to a given antigen. They do this by exchanging signals during direct, physical interactions with each other that occur throughout the response. These signals are particularly important to B cell activation and the quality of the antibodies that they produce. The nature of the signals that T cells provide to B cells, how they influence the quality of the antibody response, and, importantly, how this is in turn influenced by the target antigen, are not well understood. We propose to use engineered antigens that we have shown to naturally generate different immune outcomes as an experimental approach to work out how the immune system generates different responses. We recently identified two different antigens that produce very different B cell responses and showed that we could alter the T cell part of the antigen to influence B cell outcome. In this application, we propose to engineer variants of the well-studied NPOVA antigen and use it to directly dissect the interactions between responding B cells and the different signals they exchange to produce different immune outcomes. In the first AIM of our studies, we will use advanced microscopy to directly observe interactions between antigen-specific T and B cells in live tissue as they respond to different engineered NPOVA variants. Our pilot studies show that interaction duration and the degree to which the membranes of interacting cells become entangled is linked to the quality of the B cell response, and that this can be manipulated by altering the T cell part of the antigen. B cells produce antibodies, and interactions between T and B cells are thought to be important to improve the quality of the antibodies produced. In the second AIM, we will determine if antibody quality can be impacted through our engineered antigen variants. In the third AIM, we will identify T cell signals to B cells that are altered by our engineered antigen variants and that result in different B cell outcomes. The goal is to determine how the immune system controls the response to different antigens. These studies will be very important to our fundamental understanding of how the immune system functions, and may also inform future design of vaccines to produce more useful immune responses.