Sci. Signal., 2 August 2011
Immunology Magnesium Required?
John F. Foley
Science Signaling, AAAS, Washington, DC 20005, USA
The study of patients with rare primary immunodeficiencies, inherited defects in the immune system that render the affected individuals more susceptible to infections, often leads to the discovery of previously uncharacterized aspects of immune regulation (see commentary by Wu and Veillette). Li et al. studied two brothers with a primary immunodeficiency characterized by decreased numbers of CD4+ T cells, chronic infection by Epstein-Barr virus, and defects in T cell receptor (TCR) signaling, including Ca2+ influx. Genetic analysis revealed that the brothers harbored an X-linked defect, namely, a deletion of part of MAGT1, a gene that encodes a magnesium transporter protein (MagT1) found at the plasma membrane. Whereas TCR stimulation resulted in Mg2+ and Ca2+ influxes in T cells from normal donors, the immunodeficient T cells did not show TCR-dependent Mg2+ influx, and their Ca2+ influx was impaired. TCR stimulation of normal T cells in the absence of extracellular Mg2+ resulted in decreased Ca2+ influx; however, TCR stimulation in the absence of extracellular Ca2+ had no effect on Mg2+ influx, which, in combination with the previous data, suggested that Ca2+ influx was secondary to that of Mg2+. Knockdown of MagT1 in normal T cells by short interfering RNA (siRNA) recapitulated the TCR-stimulated Mg2+ and Ca2+ influx defects observed in T cells from the immunodeficient patients. Conversely, expression of full-length MagT1 in T cells from the immunodeficient patients restored Mg2+ influx and increased Ca2+ influx in response to TCR stimulation. Of the TCR-proximal signaling events examined in T cells from normal and immunodeficient individuals, only the activation of phospholipase C 1 (PLC-1), which is required for TCR-stimulated Ca2+ influx, was defective in the immunodeficient T cells. Furthermore, events downstream of TCR activation that were independent of PLC-1 were unaffected by MagT1 deficiency. Although the mechanisms by which TCR stimulation activates MagT1 and Mg2+ influx leads to PLC-1 activation are unclear, these data suggest that Mg2+ may act as a second messenger in the activation of T cells.
F.-Y. Li, B. Chaigne-Delalande, C. Kanellopoulou, J. C. Davis, H. F. Matthews, D. C. Douek, J. I. Cohen, G. Uzel, H. C. Su, M. J. Lenardo, Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 475, 471–476 (2011). [PubMed]
N. Wu, A. Veillette, Magnesium in a signalling role. Nature 475, 462–463 (2011). [PubMed]
Citation: J. F. Foley, Magnesium Required? Sci. Signal. 4, ec212 (2011).
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