Limited expression of TLR9 on T cells and its functional consequences in patients with nonalcoholic fatty liver disease

Background/Aims: Toll-like receptors (TLRs) modulate T cell responses in diverse diseases. Co-stimulation of T cell activation via TLR9 induces production of interferon gamma (IFN-γ), priming of which is critical for differentiation of proinflammatory macrophages. These macrophages have a crucial role in nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the expression of TLR9 protein on T cells and the consequences of TLR9-mediated triggering of these cells in patients with NAFLD. Methods: Our study included 34 patients with simple steatosis, 34 patients with nonalcoholic steatohepatitis, eight patients with NAFLD who met general diagnostic criteria but lacked histological diagnosis, and 51 control subjects. We used a synthetic TLR9 ligand to co-stimulate T cells. We measured TLR9 expression in liver and peripheral T cells and CD69 and IFN-γ as phenotypic markers of T cell activation and differentiation by flow cytometry. Results: TLR9 expression on liver and peripheral T cells was lowest in patients with simple steatosis and was positively associated with anthropometric, biochemical, and histopathological features of NAFLD. In vitro co-stimulation of T cells from patients with simple steatosis induced a limited number of IFN-γ-producing CD8+ T cells. At baseline, these patients showed a low frequency of circulating type 1 CD8+ cells. Conclusions: The positive associations between TLR9 and anthropometric, clinical, and histological features and the crucial role of IFN-γ-in NAFLD suggest that limited TLR9 expression and production of IFN-γ play a protective role in patients with simple steatosis. (Clin Mol Hepatol 2020;26:216-226)