Mg 2+ Regulates Cytotoxic Functions of NK and CD8 T Cells in Chronic EBV Infection Through NKG2D

• Published in: Science (American Association for the Advancement of Science) 2013-07, Vol.341 (6142), p.186-191
• Main Authors: Chaigne-Delalande, Benjamin, Li, Feng-Yen, O’Connor, Geraldine M., Lukacs, Marshall J., Jiang, Ping, Zheng, Lixin, Shatzer, Amber, Biancalana, Matthew, Pittaluga, Stefania, Matthews, Helen F., Jancel, Timothy J., Bleesing, Jack J., Marsh, Rebecca A., Kuijpers, Taco W., Nichols, Kim E., Lucas, Carrie L., Nagpal, Sunil, Mehmet, Huseyin, Su, Helen C., Cohen, Jeffrey I., Uzel, Gulbu, Lenardo, Michael J.
• Format: Article
• Language: English
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1240094

Individuals with X-linked immunodeficiency with Mg 2+ defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) disease are genetically deficient for expression of MAGT1 , a magnesium transporter. Chaigne-Delalande et al. (p. 186 ) sought to better understand why these individuals are chronically infected with EBV at high viral loads and are susceptible to the development of lymphomas. CD8 + T cells and natural killer cells, which help to keep EBV infection in check, exhibited reduced cytotoxicity owing to their lower expression of the cell surface receptor NKG2D, which triggers cytolysis upon ligation. Magnesium supplementation in vitro and also in two XMEN patients restored levels of free Mg 2+ , increased NKG2D expression, and resulted in reduced amounts of EBV + cells, suggesting that this may be an effective therapeutic approach for XMEN patients. Magnesium supplementation in patients with a primary immunodeficiency restores immune responses to Epstein-Barr virus. The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free magnesium (Mg 2+ ) concentrations. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. We show that decreased intracellular free Mg 2+ causes defective expression of the natural killer activating receptor NKG2D in natural killer (NK) and CD8 + T cells and impairs cytolytic responses against EBV. Notably, magnesium supplementation in MAGT1-deficient patients restores intracellular free Mg 2+ and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, these findings reveal a specific molecular function of free basal intracellular Mg 2+ in eukaryotic cells.