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

纤维化中的细胞通讯：研究组织驻留 T 细胞在人肝脏中的作用

• 批准号: MR/V02423X/1
• 负责人: Laura Pallett
• 金额: $ 142.18万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV02423X%2F1
• 关键词: Cellular; communication; fibrosis; investigating; role

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?

肝脏是我们最大的内部器官，是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控制，以防止不必要的损害。尽管肝脏在受伤时具有无与伦比的再生能力，但当肝脏试图修复和替换受损细胞时，持续的损伤或炎症可能会导致疤痕组织的沉积。这种疤痕组织的堆积(主要由称为细胞外基质蛋白的分子组成)会导致肝硬变，这在英国是一个日益严重的问题，出现在十大死因中，导致比癌症或心脏病年轻19岁的人死亡。肝脏中有许多“当地居民”或组织驻留的免疫细胞，它们提供特殊的免疫监视和保护。我最近报告了一群长寿的、驻留在组织中的T细胞，它们配备了一系列介体来控制嗜肝感染，这些感染可以根据环境的提示适应表型和功能(Pallett LJ。JEM 2017，Pallett LJ.*Gut 2019，Pallett LJ.*JEM 2020)。此外，肝脏有一组独特的基质细胞，即结缔组织细胞，当暴露在慢性损伤中时，它们成为纤维化的主要调节细胞。这些基质细胞被过度激活，并分化为能够产生过量细胞外基质蛋白的细胞。这会增加肝脏僵硬，最终导致肝功能恶化。那么，在人类肝脏中，T细胞是如何参与肝纤维化的启动和发展直至肝硬变的呢？我建议用这个UKRI FLF来探索这个问题，重点是组织驻留的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，是否有助于瘢痕组织的生成，以及我们如何利用任何涉及的途径来为患者开发改进的治疗方法？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，以期了解这些细胞如何“合作和沟通”来调节功能，以及它们是否有可能加剧或限制纤维化的发展。这将通过与皇家自由医院的研究伙伴合作，使用新分离的肝脏免疫细胞来获取组织或使用历史上保存良好的组织切片来完成。问这些关键问题：--是什么分子参与了组织驻留的T细胞和肝基质细胞的相互作用？-在T细胞和潜在的激活的基质细胞相互作用时，在慢性肝病的不同阶段驱动或分解疤痕组织的机制之间的平衡是什么？-肝脏T细胞是否影响基质细胞(反之亦然)，是通过增加它们作为疤痕组织沉积的细胞外基质的数量，还是影响它们的生存？-我们的任何发现是否可以被利用为新的免疫治疗策略，以防止人类肝脏发展为肝硬变？

项目成果

Isolation of human intrahepatic leukocytes for phenotypic and functional characterization by flow cytometry.

• DOI: 10.1016/j.xpro.2022.101356
• 发表时间: 2022-06-17
• 期刊: STAR PROTOCOLS
• 作者: Kucykowicz, Stephanie;Amin, Oliver E.;Burton, Alice R.;Swadling, Leo;Schmidt, Nathalie M.;Zakeri, Nekisa;Davies, Jessica;Aidoo-Micah, Gloryanne;Stegmann, Kerstin A.;Easom, Nicholas J.;Jeffery-Smith, Anna;Maini, Mala K.;Pallett, Laura J.
• 通讯作者: Pallett, Laura J.

Liver-resident memory T cells: life in lockdown.

• DOI: 10.1007/s00281-022-00932-w
• 发表时间: 2022-11
• 期刊: SEMINARS IN IMMUNOPATHOLOGY
• 影响因子: 9
• 作者: Pallett, Laura J.;Maini, Mala K.
• 通讯作者: Maini, Mala K.