Pro-inflammatory liver-homing T cells in peripheral blood, liver and adipose tissue in patients with NASH and changes in post-bariatric surgery samples

Background and aims: Non-alcoholic steatohepatitis (NASH), the inflammatory subtype of non-alcoholic fatty liver disease (NAFLD) associated with obesity and type2 diabetes mellitus (T2DM) can lead to advanced liver disease.There are limited data evaluating T cell subsets in multiple tissue compartments or following weight loss in NAFLD.We hypothesised that circulating and tissue T cells changed in advanced versus mild NASH.Method: Prospective samples were collected under ethicallyapproved protocols; peripheral blood from 37 NAFLD patients and 7 controls, with primary comparisons between advanced (elastography >9.7kPa or ≥F3) and mild (elastography <8.2kPa or ≤F2) NAFLD.A subset undergoing bariatric surgery (n = 21) underwent additional simultaneous sampling of liver, visceral (VAT) and subcutaneous adipose tissue (SAT) for flow cytometry immuno-profiling, with further blood samples after weight loss.Results: Peripheral blood MAIT cells were significantly reduced with greater activation in patients with advanced versus mild NAFLD or controls (0.8% vs 3.1%, 3.2% p < 0.05) although IFN gamma and TNF alpha expression was higher in all NAFLD MAIT cells (IL-17 in advanced) compared to control.In bariatric patients, Th1 (CD4 + CXCR3 + ) cells were more abundant in NASH vs no-NASH (33% vs 21% p < 0.05), particularly among patients with diabetes in whom pro-inflammatory Th1 and Th17 cells (CD4 + CD161 + ) expressed higher levels of liver homing CXCR6.After weight loss, the proportion of Th1, Th17 cells and activated (CD69 + ) CD8+ T cells reduced.The proportion of CXCR6 + Th1 and Th17 cells reduced, as did IFN gamma expressing CXCR6 + Th17 cells.In patients with T2DM NASH, intrahepatic Th17 cell numbers were higher and MAIT cells lower compared to other groups, with a similar reduction of MAIT cells in SAT.Conversely, SAT total T cell CXCR6 expression was higher in T2DM NASH than in other patient groups.In T2DM NASH, expression of tissue-retaining CD69 expression on Th1 cells was higher in the liver and lower in VAT.Conclusion: A peripheral and adipose tissue pro-inflammatory, liverhoming T cell phenotype is evident in patients with T2DM and NASH with improvement in this after weight loss.