Mutations in PI3K110δ cause impaired natural killer cell function partially rescued by rapamycin treatment.

TitleMutations in PI3K110δ cause impaired natural killer cell function partially rescued by rapamycin treatment.
Publication TypeJournal Article
Year of Publication2018
AuthorsRuiz-García, R, Vargas-Hernandez, A, Chinn, IK, Angelo, LS, Cao, TN, Coban-Akdemir, Z, Jhangiani, SN, Meng, Q, Forbes, LR, Muzny, DM, Allende, LM, Ehlayel, MS, Gibbs, RA, Lupski, JR, Uzel, G, Orange, JS, Mace, EM
JournalJ Allergy Clin Immunol
Date Published2018 08
KeywordsCell Differentiation, Cells, Cultured, Cytomegalovirus, Cytomegalovirus Infections, Cytotoxicity, Immunologic, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Heterozygote, Humans, Immunologic Deficiency Syndromes, Immunological Synapses, Immunophenotyping, Killer Cells, Natural, Lymphocyte Activation, Microscopy, Confocal, Mutation, Phosphatidylinositol 3-Kinases, Sirolimus, Viremia, Whole Exome Sequencing

BACKGROUND: Heterozygous gain-of-function mutations in PI3K110δ 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 PI3K110δ 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 Cr cytotoxicity assays, and quantitative confocal microscopy.

RESULTS: PI3K110δ 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 PI3K110δ 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.

Alternate JournalJ Allergy Clin Immunol
PubMed ID29330011
PubMed Central IDPMC6109967
Grant ListR01 AI067946 / AI / NIAID NIH HHS / United States
R01 AI120989 / AI / NIAID NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG008898 / HG / NHGRI NIH HHS / United States

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