UNRAVELLING THE CROSSTALK BETWEEN TISSUE-RESIDENT CD4+ T CELLS AND STROMAL CELLS DRIVING LIVER FIBROSIS

肝脏具有非凡的再生能力，但慢性损伤可导致不受控制的组织修复，瘢痕形成（纤维化）并最终导致器官衰竭。损伤后积聚的促纤维化介质激活驻留的基质细胞分化为异常分泌细胞外基质（ECM）的肌成纤维细胞？肝脏具有非凡的再生能力，但慢性损伤可导致不受控制的组织修复、瘢痕形成（纤维化）并最终导致器官衰竭。在损伤时积累的促纤维化介质激活驻留的基质细胞以分化成异常分泌细胞外基质（ECM）的肌成纤维细胞-这些肌成纤维细胞是纤维化的“主介质”。永久驻留在组织中的特化T细胞（组织驻留T细胞（TRM））提供有效局部免疫的能力引发了人们对利用其力量进行免疫治疗的兴趣，然而新出现的数据表明它们可能与基质细胞相互作用，并可能导致组织损伤。在健康和疾病中，肝TRM和基质细胞之间的相互作用仍然未知。因此，我假设TRM与基质细胞相互作用和交流，以交叉调节细胞分布，存活，功能和纤维化潜力，从而加剧（或限制）肝脏疾病。此外，我建议保留的'平衡'的T细胞和他们的原位定位的双向信号与底层基质细胞的影响。此外，随着纤维化的进展，我认为TRM的功能变得失调，有利于促纤维化介质的产生，从而增强肌成纤维细胞的分化。总的来说，通过了解肝脏中产生ECM的基质细胞和TRM之间的细胞串扰，这项研究旨在揭示新的抗纤维化方法，用于临床转化，以促进纤维化消退并限制ECM沉积-这是一种迫切的未满足的临床需求。

The liver has an extraordinary capacity to regenerate, yet chronic insult can lead to uncontrolled tissue repair, scarring (fibrosis) and ultimately organ failure. Profibrogenic mediators that accumulate upon injury activate resident stromal cells to differentiate into myofibroblasts aberrantly secreting extracellular matrix (ECM) ? these myofibroblasts aThe liver has an extraordinary capacity to regenerate, yet chronic insult can lead to uncontrolled tissue repair, scarring (fibrosis) and ultimately organ failure. Pro-fibrogenic mediators that accumulate upon injury activate resident stromal cells to differentiate into myofibroblasts aberrantly secrete extracellular matrix (ECM) - these myofibroblasts are the 'master mediators' of fibrosis. The ability of specialised T cells that reside permanently in tissues, tissue resident T cells (TRM), to provide efficient local immunity has ignited interest in harnessing their power for immunotherapy, however emerging data suggest they may interact with stromal cells, and may contribute to tissue damage. The interplay between hepatic TRM and stromal cells, in health and disease, remains unknown. Therefore, I hypothesise that TRM interact and communicate with stromal cells to cross-regulate cell distribution, survival, function and fibrogenic potential to exacerbate (or limit) liver disease. Moreover, I propose that the retention of 'poised' T cells and their in-situ localisation is influence by bidirectional signalling with the underlying stromal cells. In addition, as fibrosis progresses, I propose the function of TRM becomes dysregulated favouring the production of pro-fibrogenic mediators, that in turn enhance myofibroblast differentiation. Collectively, by understanding the cellular crosstalk between ECM-producing stromal cells and TRM in the liver this research aims to reveal new anti-fibrotic approaches for clinical translation to promote fibrosis regression and limit ECM deposition - an urgent unmet clinical need.