Increased frequencies of activated effector CD4+ T cells in the peripheral blood and hepatic tissue of patients with NAFL and NASH

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Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) ranges between 20 – 35% in Europe. In 5 to 20% there is a progression from non-alcoholic fatty liver (NAFL) to a non-alcoholic steatohepatitis (NASH) but it is still not understood why some people develop NASH. The current hypothesis about the pathogenesis is a two hit theory. The “first hit” causes a steatosis and the “second hit” in form of bacterial translocation leads to an inflammation and the development of NASH. Hepatic Th17 cell infiltration was observed in a NASH mouse model and higher IL-17 and IL-21 gene expression in human liver of NASH patients. We hypothesized that the phenotype of peripheral CD4+ T cells might be predictive for the degree and quality of hepatic T cell infiltration and histopathology. Aims: Characterization of CD4+ regulatory T cells (Tregs) and conventional CD4+ T cells in peripheral blood and hepatic tissue in patients with NAFL and NASH. Methods: 50 patients with histology-proven NAFL or NASH and 44 healthy controls (HC) were included in this study. PBMCs of peripheral blood and hepatic tissue were characterized by multi-colour FACS analysis. CD4+ T cells were stimulated with PMA and ionomycin for intracellular detection of cytokine production (IL-17, IL-4, INF-g, IL-21). Results: Patients were older and had a higher BMI in comparison to HC. In patients with NAFL and NASH a lower frequency of resting Tregs (CD4+CD45RA+CD25++) was observed in peripheral blood. We found changes in effector CD4+ T cells with higher frequencies of IFN-g+, IL-21+ and IL4+ cells among CD4+ T cells of the peripheral blood of patients. In hepatic tissue, higher frequency of IL17+, IFN-g+, IL21+ and IL4+ cells were measured among CD4+ T cells than in the peripheral blood. CD4+ T cells in peripheral blood and hepatic tissue contained higher frequencies of HLA-DR+, i.e. activated cells. Conclusions: The peripheral blood and hepatic tissue of patients with NAFLD contained higher frequencies of activated effector cells among CD4+ T cells. NAFL patients show a “prehepatitic” immune cell profile very similar to that seen in NASH. Our data suggest that interfering with the effector CD4+ T cell response might prevent progression from NAFL to NASH.