Investigating the function of group 3 innate lymphoid cells in the renal tract

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The kidneys play a critical role in cleaning the blood and controlling the body's water balance. Unfortunately, their function can be affected by a number of common diseases that can be life-threatening, including infection. Urinary tract infections (UTIs) are common, affecting up to half of women at some point in their lifetime. Recurrent infections can cause scarring that leads to permanent kidney damage and even kidney failure. All of the body's tissues house cells of the immune system. These sentinels stand guard in tissues and alert the body to infection by starting an inflammatory response. In the kidney, the response of immune sentinels to infection or tissue damage determines the extent of inflammation, and this can influence whether bacteria are cleared, whether there is collateral damage, and ultimately whether the function of the kidneys recovers or develops scarring. At present, we don't fully understand what type of tissue-resident immune cells live in human kidneys and bladder or their exact function. Addressing this challenge will help us to development better treatments for diseases that affect the kidney, including UTIs.In the last 5 years, a new family of immune cells have been discovered, the innate lymphoid cells (ILCs). These cells act as tissue sentinels, producing chemical signals (cytokines) that activate the immune system. One member of the ILC family, the ILC3s, have been found to be enriched in the intestine where they prevent the invasion of bacteria from the gut and produce factors that maintain the health of tissue cells. There is currently no information on whether there are ILC3s in human kidneys and bladder. We were interested in finding out if ILC3s could be important in these tissues and performed some preliminary experiments. Excitingly, we found ILC3s in mouse and human kidneys and bladder.The objective of this project is to find out what exactly they are doing, as follows:1. Where ILC3s are positioned in kidneys and bladder and whether they are situated near other immune sentinels.2. What sort of immune signalling molecules (chemokines and cytokines) are produced by ILC3s at during health and in response to the bacteria that cause UTIs. We can use mouse models and human tissues that have been donated for transplant, but cannot be used.3. How ILC3s patrol the kidney and bladder and whether they form interactions with other immune cells. To answer this question we will use a special sort of microscope and mice that have fluorescently labelled ILC3s. We have developed a protocol that allows us to image the cells in real time in the kidney and bladder, so we can begin to investigate the factors that control their movement and their interactions with other immune cells.4. Whether outcome and disease severity in UTI is affected by an absence of ILC3s, using mice that lack ILC3s due to genetic deletion of a factor that is required for their development.Elucidating the workings of ILC3s will help us to understand whether they contribute to helpful immune responses that clear bacteria in the renal tract. This will being to enable us to harness their useful functions to develop better therapeutic strategies that might reduce the frequency of UTIs or the scarring that can be associated with recurrent infections. In the long run, this could prevent patients from getting kidney failure and could help prolong the life of kidney transplants, which can also be damaged by recurrent infection.