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Second messenger role for Mg2+ revealed by human T-cell immunodeficiency

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Abstract

The magnesium ion, Mg2+, is essential for all life as a cofactor for ATP, polyphosphates such as DNA and RNA, and metabolic enzymes, but whether it plays a part in intracellular signalling (as Ca2+ does) is unknown. Here we identify mutations in the magnesium transporter gene, MAGT1, in a novel X-linked human immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. We demonstrate that a rapid transient Mg2+ influx is induced by antigen receptor stimulation in normal T cells and by growth factor stimulation in non-lymphoid cells. MAGT1 deficiency abrogates the Mg2+ influx, leading to impaired responses to antigen receptor engagement, including defective activation of phospholipase Cγ1 and a markedly impaired Ca2+ influx in T cells but not B cells. These observations reveal a role for Mg2+ as an intracellular second messenger coupling cell-surface receptor activation to intracellular effectors and identify MAGT1 as a possible target for novel therapeutics.

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Figure 1: Patients have a proximal TCR activation defect.
Figure 2: Patients have MAGT1-null mutations.
Figure 3: TCR stimulation induces a MAGT1-dependent Mg 2+ influx.
Figure 4: Requirement of receptor-stimulated Mg 2+ influx for Ca 2+ influx.
Figure 5: Knockdown and rescue of MAGT1.
Figure 6: MAGT1 deficiency impairs PLCγ1 activation upon TCR stimulation.

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Data deposits

The Illumina sequencing data has been deposited in dbGaP with accession code phs000365.v1.p1.

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Acknowledgements

We thank L. Zheng, A. Weiss, R. Germain, R. Siegel, F. Wolf and P. Schwartzberg for critically reading the manuscript; F. Wolf for advice on magnesium assessments; L. Zheng, C. Lowell and A. Weiss for advice on experiments and data; H. Jing for making HVS lines from patient cells; P. Chen for assistance with plasmid DNA preparation; N. Sandler for flow cytometry assistance; A. Snow and H. Jing for assistance with genomic DNA library preparation for Solexa sequencing; J. Almenara and Illumina staff for Solexa assistance; D. Killilea for assistance with MS-ICP data interpretation; and A. Irani for referring the patients. F.-Y.L. is in the Medical Scientist Training Program at the University of California–San Francisco and thanks K. Shannon and J. Toutolmin for support and encouragement. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health.

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Author notes

  1. Feng-Yen Li and Benjamin Chaigne-Delalande: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Development Section, Lymphocyte Molecular Genetics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Feng-Yen Li, Benjamin Chaigne-Delalande, Chrysi Kanellopoulou, Helen F. Matthews & Michael J. Lenardo

  2. Biomedical Sciences Graduate Program, University of California-San Francisco, San Francisco, 94143, California, USA

    Feng-Yen Li

  3. Human Immunological Diseases Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Jeremiah C. Davis & Helen C. Su

  4. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Daniel C. Douek

  5. Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Jeffrey I. Cohen

  6. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Gulbu Uzel

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Contributions

F.-Y.L. characterized the MAGT1 mutations and the TCR activation defect in the patients. B.C.-D. characterized the Mg2+ influx and the signalling defects. B.C.-D., F.-Y.L., H.C.S. and M.J.L. conceived and planned the experiments, and prepared the manuscript. J.C.D. performed the lyonization assay. C.K. performed the RT–PCR experiments. G.U., J.I.C. and H.C.S. referred patients and provided clinical data. H.F.M. coordinated clinical protocol and sample collection. D.C.D. provided assistance with sequencing and flow cytometry, and guided some patient assessments. All authors discussed and revised the manuscript.

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Correspondence to Michael J. Lenardo.

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Li, FY., Chaigne-Delalande, B., Kanellopoulou, C. et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 475, 471–476 (2011). https://doi.org/10.1038/nature10246

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