Defective activation of IL2-inducible T cell kinase (ITK) in XMEN disease

Abstract

Abstract We have previously described a primary immunodeficiency due to mutations in the magnesium transporter MAGT1, named XMEN disease (X-linked Magnesium defect with Epstein-Barr infection and Neoplasia). Loss of MAGT1 results in impaired T cell receptor signaling. Previous analyses suggested that proximal TCR signaling was unaffected in XMEN patients but PLCg1 phosphorylation was delayed. We have further characterized the TCR activation defect in MAGT1 deficient cells and found that the primary cause is the impaired activity of Interleukin-2 inducible T cell kinase (ITK). ITK is phosphorylated normally by LCK and recruited to immunological synapse but fails to phosphorylate downstream targets efficiently. A similar phenotype is apparent when cells from normal controls are activated in the absence of extracellular magnesium. A transient influx of magnesium is sufficient to restore ITK activity and PLCg1 phosphorylation in XMEN T cells. We are in the process of further characterizing the molecular underpinnings of ITK regulation by MAGT1. Acknowledgements: This research was supported by the Intramural Research Program of NIAID, NIH