Mutations in PI3K110? cause impaired natural killer cell function partially rescued by rapamycin treatment - 04/08/18
Abstract |
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 Cr51 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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Natural killer cell deficiency, combined immunodeficiency, cytotoxicity, activated phosphoinositide 3-kinase δ syndrome, phosphoinositide 3-kinase signaling
Abbreviations used : APDS, CD62L, JNK, ERK, IS, JNK, MTOC, mTOR, NK, PASLI, PID, PI3K, PMA, PtdIns(3,4,5)P3, PTEN, SPADE
Plan
| Supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grants R01AI067946 and R01 AI120989 (to J.S.O.), the Jeffrey Modell Foundation, the American Society of Hematology Junior Scholar Award (to E.M.M.), and NIH/National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor Hopkins Center for Mendelian Genomics. |
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| Disclosure of potential conflict of interest: I. K. Chinn's institution received a Translational Research Program Grant Award from the Jeffrey Modell Foundation for this work. S. N. Jhangiani's institution received support from the Human Genome Sequencing Center for this work. L. R. Forbes received consultancy fees from Shire, TCB, and Horizon, and her institution received grants from Chao Physician Scientist Grant for other works. D. M. Muzny's institution received a grant from the National Human Genome Research Institute (NHGRI)/National Institutes of Health (NIH) for this work, and she is employed by Baylor College of Medicine. R. A. Gibbs's institution received NIH grant UM1 HG008898 for this work. J. R. Lupski's institution received grant UM1 HG006542 from the NIH/NHGRI/National Heart, Lung, and Blood Institute (NHBLI) for this work; he personally received board membership from 23andMe (stock options) and Lasergen (stock options) and consultancy fees from Regeneron and is employed by Baylor College of Medicine. J. S. Orange received board membership from ADMA Biologics; consultancy fees from Shire/Baxalta, Griffols, CSL Behring, Walgreens, and ASD Healthcare and royalties from UpToDate. The rest of the other authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 2
P. 605 - août 2018 Retour au numéro
Article précédent
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