Harnessing tissue-resident CD8 T cells to manipulate hepatic immunity (360G-Wellcome-214191_Z_18_Z)

Hepatitis B virus (HBV) kills two thousand people a day from immune-mediated liver disease. New treatments aim to recapitulate the "functional cure" seen following natural resolution of infection, with residual virus kept under long-term immune control. Recent work has revealed that tissue-resident T-cells, which cannot be sampled in the blood, play an essential role in frontline immunosurveillance. We therefore hypothesise that profiling T-cells compartmentalised in the liver of subjects with resolved HBV will decipher mechanisms of immune control of this important human pathogen. Capitalising on unique access to intrahepatic T-cells from contrasting infection outcomes, we will define successful local immune responses to HBV. Specific aims include investigating the functional and metabolic adaptations that allow liver-resident T-cells to survive and thrive in this hostile niche, and testing strategies to induce such responses using in vitro and in vivo HBV models. To provide fundamental insights into organ-specific immunity, we will characterise the interplay between gut-translocated bacterial products and a novel population of CD14-expressing CD8+T-cells with both pro- and anti-inflammatory potential in human liver. Results will define "gold-standard" antiviral T-cells for HBV monitoring and immunotherapy and inform therapeutic manipulation of the balance between hepatic immunopathology and immunoregulation.