Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity.
Adolescent
Adult
Aged
B-Lymphocytes
/ immunology
CD8-Positive T-Lymphocytes
/ immunology
Cell Differentiation
/ genetics
Cellular Senescence
/ genetics
Child
Child, Preschool
Class I Phosphatidylinositol 3-Kinases
/ genetics
Epstein-Barr Virus Infections
/ genetics
Gain of Function Mutation
Genetic Diseases, Inborn
/ genetics
Herpesvirus 4, Human
/ immunology
Humans
Immunologic Surveillance
/ genetics
Killer Cells, Natural
/ immunology
Male
Middle Aged
CD8(+) T cells
EBV
PIK3CD
exhaustion/senescence
memory
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
02
01
2018
revised:
15
04
2018
accepted:
27
04
2018
pubmed:
26
5
2018
medline:
13
11
2019
entrez:
26
5
2018
Statut:
ppublish
Résumé
Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K-AKT-mechanistic target of rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown. Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies. We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8 PIK3CD GOF total and EBV-specific CD8 PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8
Sections du résumé
BACKGROUND
Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K-AKT-mechanistic target of rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown.
OBJECTIVE
Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies.
METHODS
We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8
RESULTS
PIK3CD GOF total and EBV-specific CD8
CONCLUSIONS
PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8
Identifiants
pubmed: 29800648
pii: S0091-6749(18)30702-4
doi: 10.1016/j.jaci.2018.04.030
pii:
doi:
Substances chimiques
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CD protein, human
EC 2.7.1.137
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
276-291.e6Informations de copyright
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. All rights reserved.