Investigating the memory CD4 T cell compartments that emerge from intestinal infection: do location and plasticity determine immune protection?

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Throughout our lifetime we will encounter an array of pathogens that succeed in entering our body and cause infections, resulting in disease and potentially damage to our tissues. In response to infection, we generate specialised immune cells termed memory cells, so named because they are equipped to rapidly respond should we ever suffer the infection again (i.e. they 'remember' the first infection and do much better the second time). The process of vaccination works because the immune system can be tricked into generating memory cells through exposure to parts of pathogens or dead versions of pathogens that cannot cause infection or disease. Vaccination and the benefit of generating memory responses has been hugely successful in targeting the childhood infections that were the scourge of humanity in the early 20th Century. The enormous value of memory cells has again been highlighted through the current coronavirus pandemic. Despite the key role memory cells play in preventing infection and disease, our understanding of different types of memory cells remains incomplete. In particular, the memory cells formed from a type of immune cell termed a CD4 T cell have been more challenging to study in experimental models. Thus key questions remain regarding the types of memory CD4 T cells that are made in certain infections and how much protection they can provide in different parts of the body. CD4 T cells are particularly relevant as they support the functions of all other immune cells. They can be considered as the conductors of the immune system, ensuring that all the other components of our complex immune systems do their jobs appropriately. This means memory CD4 T cells can have far reaching effects.Here our key goal is to improve understanding of tissue-specific CD4 memory T cells, focusing on the intestine as the largest barrier surface in the body, across which, many potential pathogens try to enter our body. Using novel models and tools developed in our lab, we can directly track what happens to different CD4 T cells and determine how this shapes the memory cells that form. We will test whether the memory cells formed following an intestinal infection stay within this tissue or are able to move throughout the body. Using different tests of their function we will build a new level of understanding of different memory CD4 T cells, filling key gaps in our knowledge. Through our research we will provide new and detailed information on how different intestinal memory populations form and what they do. In addition to understanding how we respond to intestinal infection, better descriptions of intestinal memory cells will benefit studies on intestinal inflammation. Inflammatory bowel disease affects approximately half a million people in the UK and is thought to be driven by overactive intestinal memory cells. Our improved characterisation of these cells can inform on how to potentially target these cells in patients. Furthermore, improved understanding of how memory cells form after intestinal infection can also help in the development of oral vaccines. All our current vaccines are injectable which requires technical skills and expertise in their administration that create challenges for their rapid distribution, particularly in less developed countries where health infrastructure may be lacking. In summary, our discovery research aimed at better understanding intestinal memory cells and their roles within the body has wide ranging potential benefits for human health.