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Front. Immunol. | doi: 10.3389/fimmu.2019.02000

Magnesium Restores Activity to Peripheral Blood Cells in a Patient with Functionally Impaired Interleukin-2-Inducible T Cell Kinase

Matthew Howe1, Kennichi Dowdell1,  Amitava Roy1, Julie Niemela1, Wyndham Wilson1, Joshua McElwee2, Jason Hughes2 and  Jeffrey I. Cohen1*
  • 1National Institutes of Health (NIH), United States
  • 2Merck (United States), United States

Interleukin-2-inducible T cell kinase (ITK) is critical for T cell signaling and cytotoxicity, and control of Epstein-Barr virus (EBV). We identified a patient with a novel homozygous missense mutation (D540N) in a highly conserved residue in the kinase domain of ITK who presented with EBV-positive lymphomatoid granulomatosis. She was treated with interferon and chemotherapy and her disease went into remission; however, she has persistent elevation of EBV DNA in the blood, low CD4 T cells, low NK cells, and nearly absent iNKT cells. Molecular modeling predicts that the mutation increases the flexibility of the ITK kinase domain impairing phosphorylation of the protein. Stimulation of her T cells resulted in reduced phosphorylation of ITK, PLCγ, and PKC. The CD8 T cells were moderately impaired for cytotoxicity and degranulation. Importantly, addition of magnesium to her CD8 T cells in vitro restored cytotoxicity and degranulation to levels similar to controls. Supplemental magnesium in patients with mutations in another protein important for T cell signaling, MAGT1, was reported to restore EBV-specific cytotoxicity. Our findings highlight the critical role of ITK for T cell activation and suggest the potential for supplemental magnesium to treat patients with ITK deficiency.

Keywords: ITK, Epstein - Barr virus, immune deficiency, T cell signaling, Magnesium

Received: 25 Jul 2018; Accepted: 07 Aug 2019.

Edited by:

Sylvain Latour, Centre National de la Recherche Scientifique (CNRS), France

Reviewed by:

David A. Fulcher, Australian National University, Australia
Alain Fischer, Institut National de la Santé et de la Recherche Médicale (INSERM), France  

Copyright: © 2019 Howe, Dowdell, Roy, Niemela, Wilson, McElwee, Hughes and Cohen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jeffrey I. Cohen, National Institutes of Health (NIH), Bethesda, United States, jcohen@niaid.nih.gov