A missense mutation impairs ITK function in a patient with severe Epstein-Barr virus disease.

Abstract

Abstract T cells are critical in controlling EBV. IL-2-inducible T cell kinase (ITK) is an integral component of T cell signaling and modulates cytotoxic function. ITK activation leads to ITK mediated phosphorylation of phospholipase C (PLC)-γ, resulting in an intracellular calcium flux, activation of ERK, and translocation of NF-κB and NFAT into the nucleus. ITK is expressed in cells critical for controlling EBV infection, including T cells, NK cells, and invariant NKT (iNKT) cells. Mutations in ITK have been previously reported in 9 patients, ranging from 5 to 18 years of age who presented with low numbers of CD4 T and iNKT cells and EBV driven B cell lymphoproliferation. Here we identify a patient with a previously unreported homozygous missense mutation (ITK NM_005546 c.1618G>A p.D540N) in a highly conserved residue in the kinase domain of ITK. This patient presented at age 22 with lung nodules due to lymphomatoid granulomatosis with EBV-positive large tumor cells. She was treated with interferon and cytotoxic chemotherapy and her disease ultimately went into remission. She has since had persistent elevation of EBV DNA in the blood, low CD4 T cells, low NK cells, and nearly absent iNKT cells. Stimulation of her T cells resulted in reduced ITK signaling with diminished PLC-γ and Erk activation, and impaired calcium flux. Western blot analysis showed normal levels of ITK, indicating that the mutation affects the function, but not the stability of ITK. The patient’s CD8 T cells were impaired for degranulation, while her NK cells had reduced expression of the NK cell receptor, NKG2D. Our findings highlight the critical role of ITK to modulate T cell activation and control EBV driven B cell lymphoproliferation.