Mg²⁺ regulation of kinase signaling and immune function

Mg²⁺ is required at micromolar concentrations as a cofactor for ATP, enzymatic reactions, and other biological processes. We show that decreased extracellular Mg²⁺ reduced intracellular Mg²⁺ levels and impaired the Ca²⁺ flux, activation marker up-regulation, and proliferation after T cell receptor (TCR) stimulation. Reduced Mg²⁺ specifically impairs TCR signal transduction by IL-2-inducible T cell kinase (ITK) due to a requirement for a regulatory Mg²⁺ in the catalytic pocket of ITK. We also show that altered catalytic efficiency by millimolar changes in free basal Mg²⁺ is an unrecognized but conserved feature of other serine/threonine and tyrosine kinases, suggesting a Mg²⁺ regulatory paradigm of kinase function. Finally, a reduced serum Mg²⁺ concentration in mice causes an impaired CD8⁺ T cell response to influenza A virus infection, reduces T cell activation, and exacerbates morbidity. Thus, Mg²⁺ directly regulates the active site of specific kinases during T cell responses, and maintaining a high serum Mg²⁺ concentration is important for antiviral immunity in otherwise healthy animals.