MicroRNA-146a Feedback Suppresses T Cell Immune Function by Targeting Stat1 in Patients with Chronic Hepatitis B

Abstract

More than 350 million people are chronically infected with hepatitis B virus, and dysfunctional T cell responses contribute to persistent viral infection and immunopathogenesis in chronic hepatitis B (CHB). However, the underlying mechanisms of T cell hyporesponsiveness remain largely undefined. Given the important role of microRNA-146a (miR-146a) in diverse aspects of lymphocyte function, we investigated the potential role and mechanism of miR-146a in regulating T cell immune responses in CHB. We found that miR-146a expression in T cells is significantly upregulated in CHB compared with healthy controls, and miR-146a levels were correlated with serum alanine aminotransaminase levels. Both inflammatory cytokines and viral factors led to miR-146a upregulation in T cells. Stat1 was identified as a miR-146a target that is involved in antiviral cytokine production and the cytotoxicity of CD4+ and CD8+ T cells. In vitro blockage of miR-146a in T cells in CHB greatly enhanced virus-specific T cell activity. Therefore, our work demonstrates that miR-146a upregulation in CHB causes impaired T cell function, which may contribute to immune defects and immunopathogenesis during chronic viral infection.

miR-146a suppresses cellular immune response during Japanese encephalitis virus JaOArS982 strain infection in human microglial cells

“…miR-146a targets STAT1 gene which leads to abrogation of Jak-STAT pathway [45]. We also found similar results, where miR-146a overexpression reduced the STAT1 levels and inhibition of miR-146a upregulated the STAT1 levels.…”

miR-146a negatively regulates NK cell functions via STAT1 signaling

“…23 Moreover, by targeting STAT1, miR-146a could suppress T-cell function. 20 In our study, we found a decreased amount of STAT1 in NK92-146a-over cells (Figure 4a) and an increased amount of STAT1 in NK92-146a-inh cells (Figure 4b). In addition, the level of STAT1 in primary NK cells from HDs was reduced by miR-146a (Figure 4c).…”

“…Among the miRNAs discovered, the roles of miR-146a as a negative regulator in monocyte, macrophages and T cells have been addressed. 19,20,29 However, the role of miR-146a in NK cells is still unclear.…”

“…Furthermore, in chronic hepatitis B (CHB) patients, miR-146a depresses T-cell immune function by targeting STAT1. 20 Although miR-146a is 1 of the top 20 miRNAs in NK cells, 9 its mechanisms of action on NK cell functions remain unclear.…”

microRNAs function in CD8+T cell biology

“…miR-US4-1 targets ERAP1b and thereby, interferes with the presentation of antigenic peptides to CD8 + T cells. IFNGR, IFN-gR; ifng, IFN-g. and immunopathogenesis [84]. The roles of miRNAs are only beginning to be explored in CD8 + T cell-related autoimmune diseases, in which they may be involved in regulating immune responses against self-tissues.…”