The main cause of chronic liver diseases is due to hepatitis B virus (HBV) infection, which subsequently progresses to liver cirrhosis and hepatocellular carcinoma. Elimination or persistence of the HBV infection is primarily dependent on the host’s immune response, more specifically, the response of natural killer (NK) and CD8+ cytotoxic T cells. HBV-specific CD8+ T cells contribute to eliminating the virus, however, chronic HBV-infected patients show a severely impaired CD8+ T cell phenotype and T cell dysfunction, making the cells incapable of fighting the virus. The mechanisms contributing to the CD8+ T cell failure are not well-understood and are the focus of ongoing studies.
Mg2+ concentrations are essential to regulate numerous cellular functions and enzymes, including ion channels, metabolic cycles, and intracellular signaling pathways. A key regulator of free intracellular Mg2+ levels is the magnesium transporter-1 (MAGT1), which regulates and transports free Mg2+ across the plasma membrane and, in some diseases, is required for T cell receptor (TCR)-stimulated Mg2+ influx that transiently increases free intracellular Mg2+ levels to temporarily coordinate T cell activation. Consequently, as disease progression occurs, free intracellular Mg2+ levels decrease and cause defective expression of the natural killer activating receptor (NKG2D) in NK and CD8+ T cells, leading to impaired cytolytic responses due to the inability of the NKG2D receptor to bind to the NKG2D ligand on virally infected cells. In an article by Diao et al, the authors investigate the effects of MAGT1-mediated disturbance of Mg2+ homeostasis on HBV-infected NK and CD8+ T cells.
Over a three-year investigation of patients suffering from HBV, Mg2+ levels were shown to decrease in CD8+ T cells after long term infection, but not in NK cells. Likewise, a decrease in MAGT1 expression in CD8+ T cells was apparent over the time of HBV infection, suggesting that a lack of MAGT1 leads to a decrease in plasma Mg2+ levels. Like other diseases, the decline in Mg2+ influx leads to defective NKG2D expression in infected CD8+ T cells and decreased cytotoxicity. However, Mg2+ supplementation of 40 patients with HBV infection restored Mg2+ levels and MAGT1 protein levels, signifying a possible therapeutic treatment for chronic HBV infection.
Persistent infection is characterized by impaired HBV-specific CD8+ T cell responses, however, the mechanisms responsible for CD8+ T cell failure are not well understood. This brief report aids in providing an understanding of the possible mechanisms involved in CD8+ T cell failure in HBV infection. More specifically, a decline in Mg2+ homeostasis in HBV infected CD8+ T cells over time leading to a defective expression of NKG2D. A better understanding of the mechanisms leading to viral persistence may result in new therapeutic treatment strategies that aim to remedy the T cell defects described.
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