Mutations in PI3K110? cause impaired natural killer cell function partially rescued by rapamycin treatment.

ABSTRACT: BACKGROUND:Heterozygous gain-of-function mutations in PI3K110? lead to lymphadenopathy, lymphoid hyperplasia, EBV and cytomegalovirus viremia, and sinopulmonary infections. OBJECTIVE:The known role of natural killer (NK) cell function in the control of EBV and cytomegalovirus prompted us to investigate the functional and phenotypic effects of PI3K110? mutations on NK cell subsets and cytotoxic function. METHODS:Mutations in patients were identified by using whole-exome or targeted sequencing. We performed NK cell phenotyping and functional analysis of patients' cells using flow cytometry, standard Cr51 cytotoxicity assays, and quantitative confocal microscopy. RESULTS:PI3K110? mutations led to an altered NK cell developmental phenotype and cytotoxic dysfunction. Impaired NK cell cytotoxicity was due to decreased conjugate formation with susceptible target cells and abrogated activation of cell machinery required for target cell killing. These defects were restored partially after initiation of treatment with rapamycin in 3 patients. CONCLUSION:We describe novel NK cell functional deficiency caused by PI3K110? mutation, which is a likely contributor to the severe viremia observed in these patients. Rapamycin treatment partially restores NK cell function, providing a further rationale for its use in patients with this disease.

SUBMITTER: Ruiz-Garcia R 

PROVIDER: S-EPMC6109967 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature