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J Allergy Clin Immunol. 2018 Aug;142(2):605-617.e7. doi: 10.1016/j.jaci.2017.11.042. Epub 2018 Jan 10.

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

Author information

1
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Servicio de Immunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
2
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, Houston, Tex.
3
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
6
Servicio de Immunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
7
Department of Pediatrics, Section of Pediatric Allergy and Immunology, Hamad Medical Corporation, Doha, and Department of Pediatrics, Weill Cornell Medical College, Ar-Rayyan, Qatar.
8
Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex.
9
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
10
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, Houston, Tex. Electronic address: mace@bcm.edu.

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.

KEYWORDS:

Natural killer cell deficiency; activated phosphoinositide 3-kinase δ syndrome; combined immunodeficiency; cytotoxicity; phosphoinositide 3-kinase signaling

PMID:
29330011
PMCID:
PMC6109967
DOI:
10.1016/j.jaci.2017.11.042
[Indexed for MEDLINE]
Free PMC Article

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