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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\u2013inducible 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.<\/jats:p>","DOI":"10.1084\/jem.20181970","type":"journal-article","created":{"date-parts":[[2019,6,13]],"date-time":"2019-06-13T14:44:07Z","timestamp":1560437047000},"page":"1828-1842","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":84,"title":["Mg2+ regulation of kinase signaling and immune function"],"prefix":"10.1084","volume":"216","author":[{"given":"Chryssa","family":"Kanellopoulou","sequence":"first","affiliation":[{"name":"Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 1"},{"name":"Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National 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