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]

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