Magnesium binds to enzymes and nucleic acids and is essential for their activity. It emerges that this ion can also function as a signalling molecule with a crucial role in the immune system. See Article p.471
Humans fend off offending agents such as pathogens and tumour cells using their immune system. When immune function is diminished as a result of immunodeficiencies, individuals become more susceptible to infections and, in some cases, to cancer. Immunodeficiencies can result from defects in any component of the immune system, including T cells and B cells. These disorders can be hereditary (primary immunodeficiencies) or acquired — for example, through infection with viruses such as HIV1. Although primary immunodeficiencies are rare, their study has frequently led to identification of new, and at times unsuspected, regulators of the immune system. On page 471 of this issue, Li and colleagues2 describe one such regulator, the magnesium-ion transporter MAGT1, mutations in which result in a hereditary human immunodeficiency.
T cells recognize and react to foreign antigens through T-cell receptors (TCRs) on their surface3. Antigen binding to these receptors initiates a signalling cascade, which activates the T cell, leading to a protective immune response. The cascade involves kinase enzymes, such as Lck, ZAP-70 and Itk, which, among other substrates, phosphorylate phospholipase C-γ1 (PLC-γ1). This enzyme in turn regulates intracellular levels of calcium — a crucial inducer of T-cell activation. Mutations in several proteins involved in TCR signalling, including ZAP-70 and Itk, have been discovered in patients with primary immunodeficiencies1.
Li et al.2 studied three male patients from two different families who had a new type of primary immunodeficiency. In one well-characterized family, two brothers showed chronic infection with the Epstein–Barr virus (the cause of infectious mononucleosis) from a young age. Both also had abnormally low numbers of CD4+ T cells (a subset of T cells involved in antiviral immune responses and in the control of antibody production by B cells) and showed defects in TCR signalling. The third patient had a related disorder, although the authors could not examine him as thoroughly as the others because of his untimely death.
Genetic analyses revealed that all three patients had mutations that abolished the function of the MAGT1 gene on their X chromosome. The gene's location explains why only males, which have a single copy of the X chromosome, were afflicted by the disorder. Females carrying this mutation on one of their X chromosomes usually do not show any symptoms — as was the case for the mother of the two affected brothers — but can transmit the mutations to their offspring.
The protein product of MAGT1 is the MAGT1 transporter in the cell membrane that allows magnesium ions (Mg2+) to flow into the cell4. Most of the Mg2+ in a cell is bound to DNA, to RNA, to the cellular energy carrier ATP or to enzymes, and acts as an essential cofactor for these molecules. Nonetheless, a small fraction (less than 5%) occurs as free Mg2+, and the role of this pool is poorly understood.
Li et al. show that in MAGT1-deficient patients, T cells cannot effectively increase their intracellular free Mg2+ levels in response to TCR stimulation. These cells also showed a decrease in PLC-γ1 activity and in the amount of intracellular calcium (Fig. 1). Despite these defects in T-cell activation (and abnormalities in certain responses in epithelial cells), the B cells in these patients remained unaffected.
Previous work5 has implicated free Mg2+ in T-cell activation. Li and colleagues' work now reveals the physiological relevance and the likely mechanism of this effect. Many questions remain, however. For instance, are defects in T-cell activation in MAGT1-deficient patients solely due to a problem with Mg2+ regulation? It could be that MAGT1 has other — as yet unidentified — functions, defects in which contribute to immunodeficiency.
Other questions include exactly how free magnesium influences PLC-γ1 and calcium levels in T cells. And are its effects direct, or are they indirect, occurring through another protein such as the kinase Itk? Li et al. also find that B cells do not seem to increase their intracellular levels of free Mg2+ in response to activation, even though these cells express MAGT1. Can this difference be explained by variations between the signalling machineries of B cells and T cells? Or are there, perhaps, other Mg2+ regulators that substitute for MAGT1 activity in B cells?
It will be interesting to determine which cell types — other than T cells and epithelial cells — are affected by the absence of MAGT1. A way to explore this might be to investigate whether patients deficient in this transporter show clinical manifestations other than T-cell immunodeficiency. Finally, could drugs be developed to suppress the activity of MAGT1, or of the targets of free Mg2+ within the cell, to control excessive T-cell-mediated immune responses such as those seen in human autoimmune diseases including diabetes, lupus and rheumatoid arthritis, or in transplant rejection? These questions will surely intrigue scientists and clinicians alike.
Casanova, J. L. & Abel, L. Science 317, 617–619 (2007).
Li, F. et al. Nature 475, 471–476 (2011).
Smith-Garvin, J. E., Koretzky, G. A. & Jordan, M. S. Annu. Rev. Immunol. 27, 591–619 (2009).
Zhou, H. & Clapham, D. E. Proc. Natl Acad. Sci. USA 106, 15750–15755 (2009).
Rijkers, G. T. & Griffioen, A. W. Biochem. J. 289, 373–377 (1993).
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