Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity - 04/01/19

Doi : 10.1016/j.jaci.2018.04.030

Emily S.J. Edwards, PhD ^a,^b,^{^{∗
Emily S. J. Edwards, PhD, is currently at the Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.}}, Julia Bier, MSc ^a,^b, Theresa S. Cole, MD, PhD ^c, Melanie Wong, MBBS, PhD, FRACP, FRCPA ^d,^e, Peter Hsu, FRACP, PhD ^d,^e,^g, Lucinda J. Berglund, MBBS, PhD ^e,^f,^h, Kaan Boztug, MD ⁱ, Anthony Lau, BSc ^a,^b, Emma Gostick, BSc ^j, David A. Price, MRCP, DPhil ^j,^k, Michael O'Sullivan, MBBS ^l, Isabelle Meyts, MD, PhD ^m,ⁿ, Sharon Choo, MBBS, FRACP, FRCPA ^c,^o, Paul Gray, FRACP ^e,^p, Steven M. Holland, MD ^q, Elissa K. Deenick, PhD ^a,^b,^e, Gulbu Uzel, MD ^q, Stuart G. Tangye, PhD ^a,^b,^e,^⁎
^a Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia
^b St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Darlinghurst, Australia
^c Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia
^o Immunology Laboratory, Laboratory Services, Royal Children's Hospital, Melbourne, Australia
^d Children's Hospital at Westmead, Westmead, Australia
^e CIRCA (Clinical Immunogenomics Consortia Australia), Sydney, Australia
^f Immunopathology Department, Westmead Hospital, Westmead, Australia
^g Discipline of Child and Adolescent Health, Faculty of Medicine, University of Sydney, Sydney, Australia
^h Faculty of Medicine, University of Sydney, Sydney, Australia
ⁱ CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, St Anna Children's Hospital and Children's Cancer Research Institute, Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, and Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
^j Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
^k Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Md
^l Perth Children's Hospital, Perth, Australia
^m Department of Pediatrics, University Hospital Leuven, Leuven, Belgium
ⁿ Department of Microbiology and Immunology, Childhood Immunology, KU Leuven, Leuven, Belgium
^p University of New South Wales School of Women's and Children's Health, Randwick, Australia
^q Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md

^∗Corresponding author: Stuart G. Tangye, PhD, Immunology Division, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia.Immunology DivisionGarvan Institute of Medical Research384 Victoria StDarlinghurstNSW2010Australia

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.

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Graphical abstract

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Key words : PIK3CD, CD8⁺ T cells, memory, exhaustion/senescence, EBV

Abbreviations used : CMV, GOF, LCL, mTOR, NK, PD-1, PD-L, PI3K, PMA, RICD, TAE, T_CM, TCR, T_EM, T_EMRA, T_N, T_SCM

Plan

Methods

Clinical evaluation

T, B, and NK cell phenotyping

Analysis of CD8⁺ T-cell functional capacity in vitro

Cell proliferation

Cytotoxic T-cell and NK cell killing assays (including T-cell line and NK lymphokine-activated killer cell generation)

Sorting and culture of B cells

Restimulation-induced cell death, RNA extraction, and quantitative PCR analysis

Murine flow cytometric phenotyping

Murine in vitro cultures

Statistical analysis

Results

Patients with PIK3CD GOF mutations present with features of EBV-associated disease

CD8⁺ T cells are increased and are enriched as effector memory cells in patients with PIK3CD GOF mutations

CD8⁺ T cells from patients with PIK3CD GOF mutations are skewed toward a phenotype consistent with functional exhaustion and senescence

EBV-specific CD8⁺ T cells are skewed toward a T_EM phenotype in patients with PIK3CD GOF mutations

PIK3CD GOF mutations alter the functionality of CD8⁺ T cells

Increased RICD of PIK3CD GOF CD8⁺ T cells

PIK3CD GOF mutations dysregulate NK cell differentiation and function

Altered expression of regulatory ligands on B cells in patients with PIK3CD GOF mutations

Mice bearing a PI3K p110δ GOF mutation phenocopy defects in human PIK3CD GOF CD8⁺ T cells

Discussion

Supported by the Susan and John Freeman Cancer Research Grant from Cancer Council NSW (Australia), the Office of Health and Medical Research of the NSW Government, the Jeffrey Modell Foundation, the John Cook Brown Foundation, and the National Health and Medical Research Council of Australia (1088215; 1127157). D.A.P. is a Wellcome Trust Senior Investigator. S.G.T. is a Principal Research Fellow of the NHMRC (1042925).

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 143 - N° 1

P. 276 - janvier 2019 Retour au numéro

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Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity - 04/01/19

Abstract

Background

Objective

Methods

Results

Conclusions

Graphical abstract

Plan

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