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

Abstract

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 pro-inflammatory 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<sup>+</sup> T cells. At baseline, these patients showed a low frequency of circulating type 1 CD8<sup>+</sup> 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.

TLR9 in MAFLD and NASH: At the Intersection of Inflammation and Metabolism

“…Instead of investigating a loss-of-function population, Alegre et al took the approach of identifying patients with matched parameters of metabolic dysfunction (including BMI, HOMA-IR, lipids), but who were diagnosed by biopsy with either simple steatosis or NASH (166). They focused on TLR9 expression in T cells, as intrahepatic T cells' role in NASH progression was confirmed in several studies.…”

Does limited expression of toll-like receptor 9 actually contribute to T cell activation and liver damage in nonalcoholic steatohepatitis?

“…Dear Editor, I recently read an interesting article by Alejandra et al 1 which showed the relationship between toll-like receptor 9 (TLR9), cluster of differentiation 69 (CD69) expression, and interferon-γ expression related to liver injury in patients with nonalcoholic fatty liver disease. Non-alcoholic fatty liver disease involves a comprehensive process from simple fatty liver to nonalcoholic steatohepatitis (NASH), which includes hepatocellular damage (hepatocyte ballooning) due to infiltration of inflammatory cells as well as fat accumulation, which thereby progresses to NASH-associated fibrosis and NASH-associated cirrhosis.…”

“…I have briefly summarized the results, as shown in the table below, to enhance the readers' understanding ( Table 1). 1 First, the authors analyzed TLR9 expressions in both intrahepatic and peripheral CD4 T and CD8 T cells. However, only peripheral blood mononuclear cells were used to examine the expressions of CD69 or interferon-γ.…”

Limited expression of toll-like receptor 9 on T cells and its functional consequences in patients with nonalcoholic fatty liver disease

“…Dear Editor, I read the original article titled "Limited expression of TLR9 on T cells and its functional consequences in patients with nonalcoholic fatty liver disease" by Alegre et al 1 with great interest. This article studied the role of toll-like receptor (TLR) 9 on T cells in patients with nonalcoholic fatty liver disease (NAFLD) and found positive associations between TLR9 expressions on intrahepatic CD4 + T cells, necroinflammation, and liver fibrosis.…”