Human hepatic stellate cells orchestrate the accumulation and function of CD103+ tissue-resident CD8+ T-cells in liver fibrosis

Abstract

Tissue-resident memory cells (TRM) contribute to protective and pathogenic responses in the liver, yet precisely how hepatic TRM adapt and integrate cues from the underlying stroma and extracellular matrix (ECM) in chronic liver disease (CLD) has yet to be fully defined. Here we describe a role for activated myofibroblast-like hepatic stellate cells (HSCs) in the accumulation and in situ localisation of CD8+ TRM in the CLD liver. Activated HSCs drive a program of tissue residence in activated, tissue-infiltrating CD8+ T-cells in a TGF{beta}-dependent manner. We show upregulation of CD103, ECM-binding integrins and adhesion molecules driven by TGF{beta} which together contribute to the sequestration of TRM within the ECM-rich fibrotic niche. Ex vivo, hepatic CD103+ TRM correlate with the extent of ECM deposited, express an altered repertoire of co-stimulatory and co-inhibitory receptors, transcriptional regulators of cellular exhaustion and produce less proinflammatory mediators upon TCR engagement in CLD than in health. Through expression of several co-inhibitory ligands, we further demonstrate the potential for activated HSCs to acquire an immunomodulatory phenotype and limit the capacity of CD103+ TRM to produce anti-viral and anti-tumour mediators upon antigen encounter. Finally, we demonstrate that strategies to block such regulatory pathways, including the PD1:PD-L1/PD-L2 axis, have the potential to restore the antigen-specific effector function of tissue-compartmentalised CD103+ TRM and thus contribute to improving the effectiveness of local immunosurveillance in CLD. One Sentence Summary: Activated hepatic stellate cells characteristic of liver fibrosis orchestrate an accumulation of a CD103+ TRM population with a reduced capacity for antigen-specific effector function in human CLD.