Testing the role of B cell receptor signalling in germinal centre responses

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In our highly mobile society the risks from infectious diseases are increasing due to increased travel, altered global migration and reduced security in the food-chain. Vaccination is a cost-effective approach that can protect against infection. However, vaccination does not always guarantee complete protection against infection and this is especially true in the very young and the elderly. As longevity is increasing, by 2034 it is estimated that 1 in 4 of the UK population will be aged over 65, this issue will continue to be at the forefront of preventive medicine. One of the main reasons for reduced vaccination responses is that the immune system is impaired at the extremes of age. Although poorly understood one cause is poor functioning of B cells, the immune cells that produce the antibodies that help identify and remove pathogens and thus prevent infection. Production of long lived pathogen-specific B cells is the basis of most vaccinations. When a new pathogen or vaccine enters the body B cells respond by producing antibody and importantly they are conditioned through an optimization process called "affinity maturation" to continually try to improve the quality of the antibody they make. The process is akin to evolution in that B cells undergo repeated rounds of antibody gene mutation followed by selection of the "fittest" B cells to produce antibody that will best deal with the pathogen. How affinity maturation works has been under intense scrutiny over recent years and we know that it involves B cells receiving help from other immune cell, namely T cells. What we do not understand is how the direct interaction of B cells with the pathogen or vaccine shapes this process and having this missing piece of information should allow us to develop radically different approaches to vaccinations to improve the quantity and quality of antibody produced for example in older adults. The ultimate aim of this project is to understand how this B cell and antibody selection process is regulated to allow us to produce better vaccines. This will be achieved through collaboration with the company Medimmune who will help to produce genetically modified mice where affinity maturation is enhanced. In addition to helping develop better vaccines, these mice will become valuable tools for industry in the quest to produce new monoclonal antibody therapeutics, as the process of generating new monoclonal antibodies itself involves vaccination. The link with Medimmune will ensure that their capacity in animal model generation is integrated with Dr Toellner's knowledge of B cell and vaccination biology, to produce a project that will lead to a step change in the field and generate resources useful to researchers and industry alike.