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 - 2019/1
Y1 - 2019/1
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 - Adolescent
KW - Adult
KW - Aged
KW - B-Lymphocytes/immunology
KW - CD8-Positive T-Lymphocytes/immunology
KW - Cell Differentiation/genetics
KW - Cellular Senescence/genetics
KW - Child
KW - Child, Preschool
KW - Class I Phosphatidylinositol 3-Kinases/genetics
KW - Epstein-Barr Virus Infections/genetics
KW - Gain of Function Mutation
KW - Genetic Diseases, Inborn/genetics
KW - Herpesvirus 4, Human/immunology
KW - Humans
KW - Immunologic Surveillance/genetics
KW - Killer Cells, Natural/immunology
KW - Male
KW - Middle Aged
U2 - 10.1016/j.jaci.2018.04.030
DO - 10.1016/j.jaci.2018.04.030
M3 - Article
C2 - 29800648
SN - 0091-6749
VL - 143
SP - 276-291.e6
JO - The Journal of Allergy and Clinical Immunology
JF - The Journal of Allergy and Clinical Immunology
IS - 1
ER -
