Mg2+ Regulates Cytotoxic Functions of NK and CD8 T Cells in Chronic EBV Infection Through NKG2D

Magnesium to the Rescue Individuals with X-linked immunodeficiency with Mg2+ 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 Mg2+, 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 (Mg2+) 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 Mg2+ 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 Mg2+ 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 Mg2+ in eukaryotic cells.

[1]  A. Rothe,et al.  Rescue of Impaired NK Cell Activity in Hodgkin Lymphoma With Bispecific Antibodies In Vitro and in Patients , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[2]  D. Margulies,et al.  Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion , 2012, Proceedings of the National Academy of Sciences.

[3]  J. Kutok,et al.  Immune Surveillance and Therapy of Lymphomas Driven by Epstein-Barr Virus Protein LMP1 in a Mouse Model , 2012, Cell.

[4]  S. Holland,et al.  A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. , 2011, Immunity.

[5]  S. Jonjić,et al.  Manipulation of NKG2D Ligands by Cytomegaloviruses: Impact on Innate and Adaptive Immune Response , 2011, Front. Immun..

[6]  S. Choo,et al.  Molecular Pathogenesis of EBV Susceptibility in XLP as Revealed by Analysis of Female Carriers with Heterozygous Expression of SAP , 2011, PLoS biology.

[7]  M. Lenardo,et al.  Loss of MAGT1 abrogates the Mg2+ flux required for T cell signaling and leads to a novel human primary immunodeficiency. , 2011, Magnesium research.

[8]  L. Moretta,et al.  Dual-functional capability of CD3+CD56+ CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific cytotoxicity. , 2011, Blood.

[9]  J. Coligan,et al.  Complex regulation of human NKG2D-DAP10 cell surface expression: opposing roles of the γc cytokines and TGF-β1. , 2011, Blood.

[10]  D. Douek,et al.  Second messenger role for Mg2+ revealed by human T-cell immunodeficiency , 2011, Nature.

[11]  A. Perraud,et al.  The Mg2+ transporter MagT1 partially rescues cell growth and Mg2+ uptake in cells lacking the channel‐kinase TRPM7 , 2011, FEBS letters.

[12]  K. Nichols,et al.  Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies. , 2011, The Journal of allergy and clinical immunology.

[13]  K. Nichols,et al.  X‐linked lymphoproliferative syndrome: a genetic condition typified by the triad of infection, immunodeficiency and lymphoma , 2011, British journal of haematology.

[14]  S. Calattini,et al.  Detection of EBV genomes in plasmablasts/plasma cells and non-B cells in the blood of most patients with EBV lymphoproliferative disorders by using Immuno-FISH. , 2010, Blood.

[15]  A. Snow,et al.  X-linked lymphoproliferative syndromes: brothers or distant cousins? , 2010, Blood.

[16]  F. Wolf,et al.  TRPM7 and magnesium, metabolism, mitosis: An old path with new pebbles , 2010, Cell cycle.

[17]  G. Quamme.  Molecular identification of ancient and modern mammalian magnesium transporters. , 2010, American journal of physiology. Cell physiology.

[18]  A. Sharland,et al.  NKG2D and its ligands. , 2009, The international journal of biochemistry & cell biology.

[19]  D. Clapham,et al.  Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development , 2009, Proceedings of the National Academy of Sciences.

[20]  M. Schweigel,et al.  Expression and functional activity of the Na/Mg exchanger, TRPM7 and MagT1 are changed to regulate Mg homeostasis and transport in rumen epithelial cells. , 2008, Magnesium research.

[21]  N. Greenberg,et al.  NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. , 2008, Immunity.

[22]  Eric O Long,et al.  Activation, coactivation, and costimulation of resting human natural killer cells , 2006, Immunological reviews.

[23]  E. Wang,et al.  The Switch from Latent to Productive Infection in Epstein-Barr Virus-Infected B Cells Is Associated with Sensitization to NK Cell Killing , 2006, Journal of Virology.

[24]  F. Baldanti,et al.  Successful In Vitro Priming of EBV‐Specific CD8+ T Cells Endowed with Strong Cytotoxic Function from T Cells of EBV‐Seronegative Children , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[25]  M. Smyth,et al.  NKG2D and cytotoxic effector function in tumor immune surveillance. , 2006, Seminars in immunology.

[26]  L. Lanier,et al.  NKG2D in NK and T Cell-Mediated Immunity , 2005, Journal of Clinical Immunology.

[27]  A. Thrasher,et al.  SAP mediates specific cytotoxic T-cell functions in X-linked lymphoproliferative disease. , 2004, Blood.

[28]  D. Thorley-Lawson,et al.  Persistence of the Epstein-Barr virus and the origins of associated lymphomas. , 2004, The New England journal of medicine.

[29]  James F. Jones,et al.  Autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for the treatment of persistent active EBV infection. , 2002, Blood.

[30]  J. Orange.  Human natural killer cell deficiencies and susceptibility to infection. , 2002, Microbes and infection.

[31]  B. Totapally,et al.  Magnesium sulfate administered via continuous intravenous infusion in pediatric patients with refractory wheezing. , 2002, Journal of critical care.

[32]  A. Diefenbach,et al.  The role of the NKG2D immunoreceptor in immune cell activation and natural killing. , 2002, Immunity.

[33]  Adelheid Cerwenka,et al.  Natural killer cells, viruses and cancer , 2001, Nature Reviews Immunology.

[34]  S. Riddell,et al.  Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells , 2001, Nature Immunology.

[35]  E. Gracely,et al.  A randomized trial of magnesium in the emergency department treatment of children with asthma. , 2000, Annals of emergency medicine.

[36]  M. Colonna,et al.  Patients with X‐linked lymphoproliferative disease have a defect in 2B4 receptor‐mediated NK cell cytotoxicity , 2000, European journal of immunology.

[37]  S. Reinert,et al.  Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma. , 2000, Archives of pediatrics & adolescent medicine.

[38]  J. Cohen.  Epstein-Barr Virus Infection , 2000 .

[39]  M. Shannon,et al.  Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial. , 1996, The Journal of pediatrics.

[40]  H. Rubin.  Central role for magnesium in coordinate control of metabolism and growth in animal cells. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S. Fulda,et al.  The cytotoxic potential of interleukin-15-stimulated cytokine-induced killer cells against leukemia cells. , 2012, Cytotherapy.

[42]  Eric O Long,et al.  Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. , 2006, Blood.

[43]  M. Maguire,et al.  Magnesium as a regulatory cation: criteria and evaluation. , 1987, Magnesium.