Mutation of the magnesium transporter 1 (MAGT1) gene results in a primary immunodeficiency known as XMEN (X-linked immunodeficiency with Mg2+ defect, EBV infection and neoplasia). MAGT1 selectively transports Mg2+ ions across the plasma membrane into cells, but it has been unclear how the decreased intracellular levels of free (unbound) Mg2+ in patients with XMEN account for the high levels of Epstein–Barr virus (EBV) and hence the predisposition to lymphoma. This study in Science shows that intracellular free Mg2+ is required for the cytotoxic activity of T cells and natural killer (NK) cells as it controls the expression of the activating receptor natural killer group 2 member D (NKG2D).
The authors studied seven patients with XMEN, all of whom had increased levels of EBV DNA in their blood compared with control individuals, and some of whom had developed lymphoproliferative disorders including lymphoma. NK cells and EBV-specific cytotoxic T lymphocytes (CTLs) from these patients showed defective cytotoxicity against target cells in vitro, which could not be explained by a deficient production of cytotoxic granule proteins or degranulation.
NK cells and CTLs from the patients with XMEN had a selective loss of expression of NKG2D but not of other NK cell receptors. This was not a secondary effect of EBV infection as NKG2D loss was not observed in patients with chronic active EBV infection. The loss of NKG2D expression in patients with XMEN decreased the NK cell- and CTL-mediated killing of target cell lines expressing the NKG2D ligand UL16-binding protein 1 (ULBP1; also known as NKG2D ligand 1). This cytotoxicity defect in patients with XMEN could be almost completely rescued in NK cells and partly rescued in CTLs by Mg2+ supplementation during culture, which resulted in increased intracellular free Mg2+ and increased NKG2D expression. The effect of Mg2+ supplementation on cytotoxicity could be abrogated by a blocking antibody specific for NKG2D, which shows that it is specifically mediated by this receptor.
To test the hypothesis that defective control of EBV in patients with XMEN is a result of defective NKG2D-mediated killing of infected cells, two of the patients were given a Mg2+ supplement in various forms. The combined results showed that Mg2+ supplementation can increase intracellular free Mg2+ levels, increase NKG2D expression and decrease the fraction of B cells that are positive for EBV. The effects of Mg2+ supplementation on NKG2D expression levels and the fraction of EBV-positive B cells were reversible, which indicates that continuous supplementation might be required for clinical use. Of note, EBV strongly upregulates the expression of NKG2D ligands by infected cells compared with other viruses such as cytomegalovirus, which might account for the selective loss of control of EBV in patients with XMEN.
In addition to suggesting a possible therapy for patients with XMEN, these results show an important role for free basal Mg2+ concentration in regulating cytotoxic immune responses.