Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity

Emily S.J. Edwards, Julia Bier, Theresa S. Cole, Melanie Wong, Peter Hsu, Lucinda J. Berglund, Kaan Boztug, Anthony Lau, Emma Gostick, David A. Price, Michael O'Sullivan, Isabelle Meyts, Sharon Choo, Paul Gray, Steven M. Holland, Elissa K. Deenick, Gulbu Uzel, Stuart G. Tangye

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

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+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV. Results: PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70. Conclusions: PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
DOIs
Publication statusAccepted/In press - 1 Jan 2018

Keywords

  • CD8 T cells
  • EBV
  • exhaustion/senescence
  • memory
  • PIK3CD

Cite this

Edwards, Emily S.J. ; Bier, Julia ; Cole, Theresa S. ; Wong, Melanie ; Hsu, Peter ; Berglund, Lucinda J. ; Boztug, Kaan ; Lau, Anthony ; Gostick, Emma ; Price, David A. ; O'Sullivan, Michael ; Meyts, Isabelle ; Choo, Sharon ; Gray, Paul ; Holland, Steven M. ; Deenick, Elissa K. ; Uzel, Gulbu ; Tangye, Stuart G. / Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity. In: Journal of Allergy and Clinical Immunology. 2018.
@article{2b63a183a1a241d39b3dc7aef340038a,
title = "Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity",
abstract = "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+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV. Results: PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70. Conclusions: PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.",
keywords = "CD8 T cells, EBV, exhaustion/senescence, memory, PIK3CD",
author = "Edwards, {Emily S.J.} and Julia Bier and Cole, {Theresa S.} and Melanie Wong and Peter Hsu and Berglund, {Lucinda J.} and Kaan Boztug and Anthony Lau and Emma Gostick and Price, {David A.} and Michael O'Sullivan and Isabelle Meyts and Sharon Choo and Paul Gray and Holland, {Steven M.} and Deenick, {Elissa K.} and Gulbu Uzel and Tangye, {Stuart G.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.jaci.2018.04.030",
language = "English",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Elsevier",

}

Edwards, ESJ, Bier, J, Cole, TS, Wong, M, Hsu, P, Berglund, LJ, Boztug, K, Lau, A, Gostick, E, Price, DA, O'Sullivan, M, Meyts, I, Choo, S, Gray, P, Holland, SM, Deenick, EK, Uzel, G & Tangye, SG 2018, 'Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2018.04.030

Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity. / Edwards, Emily S.J.; Bier, Julia; Cole, Theresa S.; Wong, Melanie; Hsu, Peter; Berglund, Lucinda J.; Boztug, Kaan; Lau, Anthony; Gostick, Emma; Price, David A.; O'Sullivan, Michael; Meyts, Isabelle; Choo, Sharon; Gray, Paul; Holland, Steven M.; Deenick, Elissa K.; Uzel, Gulbu; Tangye, Stuart G.

In: Journal of Allergy and Clinical Immunology, 01.01.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity

AU - Edwards, Emily S.J.

AU - Bier, Julia

AU - Cole, Theresa S.

AU - Wong, Melanie

AU - Hsu, Peter

AU - Berglund, Lucinda J.

AU - Boztug, Kaan

AU - Lau, Anthony

AU - Gostick, Emma

AU - Price, David A.

AU - O'Sullivan, Michael

AU - Meyts, Isabelle

AU - Choo, Sharon

AU - Gray, Paul

AU - Holland, Steven M.

AU - Deenick, Elissa K.

AU - Uzel, Gulbu

AU - Tangye, Stuart G.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV. Results: PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70. Conclusions: PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.

AB - 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+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV. Results: PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70. Conclusions: PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.

KW - CD8 T cells

KW - EBV

KW - exhaustion/senescence

KW - memory

KW - PIK3CD

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U2 - 10.1016/j.jaci.2018.04.030

DO - 10.1016/j.jaci.2018.04.030

M3 - Article

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

ER -