Αρχειοθήκη ιστολογίου

Αλέξανδρος Γ. Σφακιανάκης
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5
Άγιος Νικόλαος Κρήτη 72100
2841026182
6032607174

Τετάρτη 23 Μαΐου 2018

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

Publication date: Available online 22 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): 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
BackgroundGermline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphatidylinositol-3 kinase, result in hyperactivation of the PI3K-AKT-mTOR pathway and underlie a novel inborn error of immunity. Affected individuals exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or CMV infection, and an increased incidence of B-cell lymphoproliferation and/or lymphoma. Mechanisms underlying disease pathogenesis remain unknown.ObjectiveUnderstanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in individuals with PIK3CD GOF mutations, identify key molecules required for cell mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this as well as other EBV-opathies.MethodsWe studied the consequences of PIK3CD GOF mutations on the generation, differentiation and function of CD8+ T cells and NK cells, which are implicated in host defense against infection with herpesviruses including EBV.ResultsPIK3CD GOF total and EBV-specific CD8+ T cells were skewed towards an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion, and increased susceptibility to re-activation induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF. NK cells in PIK3CD GOF individuals also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T cells and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, PDL-1/2 and CD70.ConclusionsPIK3CD GOF mutations aberrantly induce exhaustion and/or senescence and impair cytotoxicity of CD8+ T and NK cells. These defects may contribute to clinical features of affected individuals, such as impaired immunity to herpesviruses and tumor surveillance.

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