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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 and Tangye, Stuart G. 2019. Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity. Journal of Allergy and Clinical Immunology 143 (1) , pp. 276-291. 10.1016/j.jaci.2018.04.030
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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Elsevier
ISSN: 0091-6749
Date of First Compliant Deposit: 13 August 2018
Date of Acceptance: 27 April 2018
Last Modified: 14 Feb 2019 13:41
URI: http://orca.cf.ac.uk/id/eprint/114156

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