Abstract

The MAGT1 transporter is critically involved in the selective regulation of intracellular free Mg2+ levels in mammalian cells. The molecular functions of free Mg2+ in eukaryotic cells have not been established. We found that patients with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. In studying lymphocytes from these patients, we found that a deficiency of MAGT1 caused decreased basal intracellular free Mg2+ leading to defective expression of the natural killer activating receptor NKG2D in NK and CD8+ T cells. Without NKG2D, cytolytic responses against EBV are diminished, thereby revealing the first specific molecular function of intracellular basal free Mg2+ in eukaryotic cells. Moreover, intracellular free Mg2+, NKG2D expression and function can be rescued in vitro by incubating patient cells and elevated levels of Mg2+. Moreover, NKG2D expression and cytolytic function can be improved and EBV-infected cells reduced in vivo, in MAGT1-deficient patients by magnesium administration. Thus, our data indicate an important molecular function for free basal Mg2+ in immunity and demonstrate a requirement for NKG2D cytolytic function in an essential EBV antiviral response in humans.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAI001187-01
Application #
8745601
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2013
Total Cost
$418,961
Indirect Cost

  Institution

Name
National Institute of Allergy and Infectious Diseases
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Juan, Ravell; Otim, Isaac; Nabalende, Hadijah et al. (2018) Plasma magnesium is inversely associated with Epstein-Barr virus load in peripheral blood and Burkitt lymphoma in Uganda. Cancer Epidemiol 52:70-74
Brigida, Immacolata; Chiriaco, Maria; Di Cesare, Silvia et al. (2017) Large Deletion of MAGT1 Gene in a Patient with Classic Kaposi Sarcoma, CD4 Lymphopenia, and EBV Infection. J Clin Immunol 37:32-35
Ozen, Ahmet; Comrie, William A; Ardy, Rico C et al. (2017) CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med 377:52-61
Abolhassani, Hassan; Edwards, Emily S J; Ikinciogullari, Aydan et al. (2017) Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. J Exp Med 214:91-106
Li, Feng-Yen; Chaigne-Delalande, Benjamin; Rao, V Koneti et al. (2015) Clinical utility gene card for: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN). Eur J Hum Genet 23:
Ravell, Juan; Chaigne-Delalande, Benjamin; Lenardo, Michael (2014) X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia disease: a combined immune deficiency with magnesium defect. Curr Opin Pediatr 26:713-9
Chaigne-Delalande, Benjamin; Lenardo, Michael J (2014) Divalent cation signaling in immune cells. Trends Immunol 35:332-44
Li, Feng-Yen; Chaigne-Delalande, Benjamin; Su, Helen et al. (2014) XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood 123:2148-52
Chaigne-Delalande, Benjamin; Li, Feng-Yen; O'Connor, Geraldine M et al. (2013) Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science 341:186-91
Lo, Bernice; Ramaswamy, Madhu; Davis, Joie et al. (2013) A rapid ex vivo clinical diagnostic assay for fas receptor-induced T lymphocyte apoptosis. J Clin Immunol 33:479-88

Showing the most recent 10 out of 14 publications