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

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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.