Cellular communication in fibrosis: investigating the role of tissue-resident T cells in the human liver

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The liver is our largest internal organ that acts as a central hub of many physiological processes. Immune responses within the liver are therefore tightly regulated to prevent unnecessary damage. Although the liver has an unrivalled ability to regenerate when injured, persistent injury or inflammation can result in the deposition of scar tissue as the liver attempts to repair and replace damaged cells. This build-up of scar tissue (largely made up of molecules called extracellular matrix proteins) results in liver cirrhosis, which represents a growing problem in the UK, appearing in the top ten causes of death and killing individuals 19 years younger than cancer or heart disease. The liver harbours a number of 'local residents' or tissue-resident immune cells that provide specialised immune-surveillance and protection. I recently reported a population of long-lived, tissue-resident T cells equipped with an armoury of mediators to control hepatotropic infections that can adapt phenotypically and functionally depending on cues from their environment (Pallett LJ. JEM 2017, Pallett LJ.* Gut 2019, Pallett LJ.* JEM 2020). In addition, the liver has a unique population of stromal cells, the connective tissue cells, that when exposed to chronic injury become the master regulators of fibrosis. These stromal cells get overactivated and differentiate into a cell capable of producing excessive amounts of extracellular matrix proteins. This increases liver stiffness and ultimately a deterioration in liver function. So how are T cells involved in fibrosis initiation and development through to cirrhosis in the human liver? I propose with this UKRI FLF to probe this question focussing on how tissue-resident T cells and the stromal cells interact in the healthy and diseased human liver. Do these local hepatic T-cells, these immune sentinels, contribute to the generation of scar tissue and how can we harness any pathway involved to develop improved treatment approaches for patients? To address these central questions, I will study in detail the interaction of these two cells types with a view to understanding how these cells 'co-operate and communicate' to regulate function and any potential they have to exacerbate or limit the development of fibrosis. This will be done using freshly isolated hepatic immune cells in collaboration with research partners at the Royal Free Hospital to access tissue or using historical well-preserved tissue sections. Asking these key questions: -- What are the molecules involved in allowing tissue-resident T cells and hepatic stromal cells to interact?- Upon interaction of T-cells and the underlying activated stromal cells, what is the balance between the mechanisms driving or resolving scar tissue at the various stages of chronic liver disease?- Do hepatic T-cells influence stromal cells (or vice versa), either by increasing the amount of extracellular matrix they lay down as scar tissue, or influencing their survival?- Can any of our findings be harnessed as novel immuno-therapeutic strategies to prevent the development of cirrhosis in the human liver?