Mg2+ regulation of kinase signaling and immune function

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