Cell-intrinsic roles of P110delta in primary and memory antibody responses

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The production of antibodies is critical for immunity and is one of the key processes stimulated by vaccination. Vaccine failure, which becomes more common upon ageing, is largely due to a failure to elicit antibodies. Antibodies are secreted by specialised cells called plasma cells which are the descendents of the B-lymphocyte, a specialized (differentiated) form of white blood cell. Our study is aimed at understanding how the process of B lymphocyte differentiation is regulated in the mammal. Despite great effort, this cannot be mimicked by culturing cells in specialized media and incubators. Therefore we have to use animal models; in this case we use the mouse, partly because we have a great many research tools to study B lymphocyte differentiation in detail and also because we already know much about the system including how it is similar to other animals. This allows us to ask and examine sophisticated questions. We already know that when B lymphocytes are stimulated by antigen they may either quickly differentiate into antibody secreting plasma cells, which reside in a specific anatomical location. Alternatively they may become rapidly proliferating, but non-antibody secreting, germinal centre cells. Each of these two alternative cell fates is regulated by second type of cell called the T-lymphocyte. Our study is concerned with characterising the T-lymphocytes which promote each of these B cell fate decisions. To provoke an immune response, mice will be challenged with model antigens including an attenuated (not-virulent) form of salmonella. The responses to these challenges will be measured to count the numbers of each type of different cell and determine their precise anatomical location. The process will be perturbed by specifically targeting mutations of a cell activation pathway to the T cells; all other cells, including the B lymphocytes, will remain normal allowing us to conclude that any altered behaviour B lymphocytes display will be due to a defect in the T cells.