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

肝脏是我们最大的内部器官，作为许多生理过程的中心枢纽。因此，肝脏内的免疫反应受到严格调节，以防止不必要的损害。虽然肝脏在受伤时具有无与伦比的再生能力，但持续的损伤或炎症会导致疤痕组织沉积，因为肝脏试图修复和替换受损细胞。这种疤痕组织的积累（主要由称为细胞外基质蛋白的分子组成）导致肝硬化，这在英国是一个日益严重的问题，出现在十大死亡原因中，比癌症或心脏病年轻19岁。肝脏拥有许多“本地居民”或组织驻留免疫细胞，提供专门的免疫监视和保护。我最近报道了一群长寿的、组织驻留的T细胞，其配备有一系列介质以控制嗜肝性感染，其可以根据来自其环境的线索在表型和功能上适应（Pallett LJ. JEM 2017，Pallett LJ.* Gut 2019，Pallett LJ.* JEM 2020）。此外，肝脏具有独特的基质细胞群，即结缔组织细胞，当暴露于慢性损伤时，其成为纤维化的主要调节者。这些基质细胞被过度激活并分化成能够产生过量细胞外基质蛋白的细胞。这会增加肝脏硬度，最终导致肝功能恶化。那么T细胞是如何参与肝纤维化的发生和发展直至肝硬化的呢？我建议用这个UKRI FLF来探讨这个问题，重点是组织驻留T细胞和基质细胞如何在健康和患病的人类肝脏中相互作用。这些局部的肝脏T细胞，这些免疫哨兵，是否有助于疤痕组织的产生？我们如何利用任何相关的途径来为患者开发更好的治疗方法？为了解决这些核心问题，我将详细研究这两种细胞类型的相互作用，以了解这些细胞如何“合作和交流”来调节功能以及它们加剧或限制纤维化发展的任何潜力。这将使用新鲜分离的肝脏免疫细胞与皇家自由医院的研究伙伴合作来获取组织或使用历史保存良好的组织切片来完成。提出这些关键问题：--什么分子参与了组织驻留T细胞和肝基质细胞的相互作用？在T细胞和潜在的活化基质细胞相互作用后，在慢性肝病的各个阶段驱动或解决疤痕组织的机制之间的平衡是什么？肝T细胞是否会影响基质细胞（反之亦然），无论是通过增加细胞外基质的数量，他们奠定了疤痕组织，或影响他们的生存？我们的任何发现都可以作为新的免疫治疗策略来预防人类肝硬化的发展吗？

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?