Stop the clock on chronic inflammation

In health, self-reactive T-cells are controlled by Foxp3+Regulatory T-cells (Treg) through a process termed dominant tolerance. In life-threatening autoimmune diseases, pathogenic T-cells escape this immune regulation by responding to self-antigens, which results in tissue damage and loss of organ function. The importance of Treg, and an indication of their efficacy as potential cellular-therapies for autoimmune disease, is clear from the severe autoimmunity that is triggered by their absence. Despite this, knowledge of the chronic inflammation mechanisms that occur within tissues and are caused by immune dysregulation is incomplete, and this significantly limits approaches to restore immune homeostasis in target tissues. By focussing on autoimmune liver diseases, we will determine mechanisms of disease-causing immune dysregulation. Our overarching hypothesis is that chronic inflammation is caused by loss of regulatory T-cells control of stemlike-progenitor, effector T-cells in hostile tissue environment. Recent observations correlate Tertiary Lymphoid Structures(TLS) with pathological immune responses in autoimmune diseases, thus we will focus on chronic inflammation driven by stemlike-effector T-cells residing in TLS within inflamed tissues. In addition, we will use approaches to enable stable functional 'armoured' Treg to control unwanted T-cell responses and create a favourable tissue microenvironment to stop chronic inflammation and restore peripheral tissue tolerance.