Unravelling the Crosstalk Between Tissue-Resident CD4+ T Cells and Stromal Cells Driving Liver Fibrosis

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.