Mg(2+) regulation of kinase signaling and immune function

Mg(2+) is required at micromolar concentrations as a cofactor for ATP, enzymatic reactions, and other biological processes. We show that decreased extracellular Mg(2+) reduced intracellular Mg(2+) levels and impaired the Ca(2+) flux, activation marker up-regulation, and proliferation after T cell receptor (TCR) stimulation. Reduced Mg(2+) specifically impairs TCR signal transduction by IL-2–inducible T cell kinase (ITK) due to a requirement for a regulatory Mg(2+) in the catalytic pocket of ITK. We also show that altered catalytic efficiency by millimolar changes in free basal Mg(2+) is an unrecognized but conserved feature of other serine/threonine and tyrosine kinases, suggesting a Mg(2+) regulatory paradigm of kinase function. Finally, a reduced serum Mg(2+) concentration in mice causes an impaired CD8(+) T cell response to influenza A virus infection, reduces T cell activation, and exacerbates morbidity. Thus, Mg(2+) directly regulates the active site of specific kinases during T cell responses, and maintaining a high serum Mg(2+) concentration is important for antiviral immunity in otherwise healthy animals.