Loss of MAGT1 abrogates the Mg2+ flux required for T cell signaling and leads to a novel human primary immunodeficiency

Although Mg2+ has a well-recognized role as an essential cofactor for all ATP-binding enzymes, its role as a signaling ion, like Ca2+, has been controversial. A requirement for Mg2+ for optimal T lymphocyte stimulation was demonstrated more than 30 years ago, but the mechanism of its synergistic effect with Ca2+ in T cell activation remains elusive. Here, we summarize our recent discovery of a signaling role for Mg2+ in the T cell antigen receptor (TCR) signaling pathway from the study of a novel primary immunodeficiency, now named X-linked immunodeficiency with Mg2+ defect, EBV infection and neoplasia (XMEN). XMEN patients were found to have a deficiency in magnesium transporter 1 (MAGT1), an Mg2+-specific transporter, which leads to the absence of a TCR-stimulated Mg2+ flux and an attenuation of T cell activation. We further showed that this Mg2+ flux is required proximally for the temporal orchestration of phospholipase C-gamma 1 (PLC gamma 1) activation. Thus, our study not only provides a second messenger role for Mg2+ to explain its synergism with calcium in T cell signaling, it also identifies a potential extracellular therapeutic target for T cell-specific immunomodulation.