Characterisation of lymphocyte function during tissue regeneration and natural ageing

The completion of this project will help us to understand the effect adaptive immune cells have after a tissue is injured. We are born with cells of our innate immune system but our adaptive immune system develops over time and "learns" and "remembers" pathogens we encounter throughout our lives. The adaptive immune response is vital for fighting off many different infections and is made up of several different types of specialist cells which work together to protect us. Cells of our innate immune system, such as neutrophils and macrophages, fight infections too but are also vital in the response to tissue damage, helping injuries to heal in many different ways. The function of both our innate and adaptive immune system can decline as we get older, potentially affecting how well we can heal after injury.

Some animals, such as zebrafish, are able to fully replace cells that were damaged or died as a result of an injury, without forming permanent scars, and innate immune cells like macrophages are vital for allowing this to happen. This suggests that understanding cells of the zebrafish immune system may hold the key to encouraging cells and organs of other animals to repair better or even regenerate. Certain types of adaptive immune cells (lymphocytes) influence these innate immune cells and this can both help and hinder the response to injury. Whether these lymphocytes are helpful or harmful to injury repair depends on several different factors, such as the type of cell being studied, the organ they are in or the type of injury, but we do not fully understand all these complex factors. For a long time it was thought that animals such as zebrafish had a less complex immune system than us and that was a reason why they can regenerate but mammals like us can't. However, we now know that zebrafish have very similar immune cells to us and we have shown that zebrafish lymphocytes also respond to an injury. The more we can learn about how zebrafish immune cells, including lymphocytes, can benefit regeneration the closer we could be to understanding how natural regeneration works and finding ways to encourage our cells to regenerate too.

Currently, there have been very few studies into lymphocytes in any animals that can regenerate and so this project aims to address this gap in our knowledge. We will thoroughly map the different lymphocytes that respond to different types of injury in an adult zebrafish, investigate the effect of the loss of these cells on injury repair and regeneration and evaluate what happens to these cells as the fish get older. The completion of this project would provide much more information on how all different types of immune cells work together to facilitate tissue regeneration in zebrafish, helping us to identify better ways to promote injury repair in all animals.

Adult zebrafish can fully regenerate many different tissues including the skin and heart. Our group and others have shown precise roles for macrophage populations following injury to the heart including regulation of neovascularisation, promoting cardiomyocyte proliferation, and driving scar deposition and scar removal. The interaction between innate and adaptive immune cells in the infection response is well characterised but the collaboration of these cells in the response to tissue injury is not well understood. Some studies have investigated precise lymphocyte populations in mammalian tissue injury but these studies report contradictory beneficial and detrimental effects and the studies in regenerative models are even more scant. One prevailing hypothesis is that regeneration is aided by a more immature immune system and this is supported by the regenerative ability of larval and neonatal forms. However, our data from adult zebrafish demonstrate that lymphocyte populations respond to injury in the skin and heart in a similar temporal manner to that observed in mammals, but we do not currently understand the role of these cells in the regenerative response. In this discovery science proposal we aim to address this gap in our knowledge. We will comprehensively determine the frequency of different subsets during the repair and regeneration timeline and determine their functional roles using mutant lines lacking different populations. Finally, our preliminary data suggest that natural ageing results in aberrant lymphocyte distribution and limits regenerative capacity so we will investigate the correlation between these two phenotypes. Overall, the completion of this project will greatly increase our understanding of the collaborative roles of different inflammatory cell populations in tissue regeneration.