A pathogenic role for regulatory T cells in chronic liver disease

Abstract Current dogma holds that regulatory T (Treg) cells preserve tissue function in settings of inflammation and damage through their anti-inflammatory activity and production of epithelial growth factors – the latter of which is independent from immunosuppression. Consistent with this, we observe that Treg cells – in particular those producing the epidermal growth factor receptor (EGFR)-ligand amphiregulin (Areg) – are enriched in the livers of mice and humans with non-alcoholic steatohepatitis (NASH). Mouse and human liver Treg cells undergo substantial transcriptional changes in chronic liver damage, reflecting their increased activation; however, rather than playing a protective role, we find that Treg cell–derived Areg promotes NASH-induced liver fibrosis through the direct activation of EGFR on hepatic stellate cells. Clinically, NASH is closely linked to insulin resistance, but the mechanistic contributions of NASH-induced disease processes to insulin resistance remain unclear. We further observe that Treg cell–derived Areg promotes glucose intolerance in a NASH-dependent manner – through the induction of hepatic gluconeogenesis – a process also mediated through EGFR signaling on hepatic stellate cells. Mechanistically, Treg cell–derived Areg promotes hepatocyte gluconeogenesis through hepatocyte detection of soluble mediators produced by Areg-activated hepatic stellate cells – offering new insight into how chronic liver disease promotes insulin resistance. Taken together, we provide the first evidence that Treg cells mediate a maladaptive role in tissue injury, finding that their production of a growth factor plays a central role in liver disease and promotes liver fibrosis and glucose intolerance in NASH. This research was supported by grants from NIH (K22 AI127847, R01 HL148718, R01 CA259634, T32 GM007367, P30 CA013696, P30 DK132710) and the Searle Scholars Program (SSP-2017-2179).