Emily S J Edwards1, Julia Bier1, Theresa S Cole2, Melanie Wong3, Peter Hsu4, Lucinda J Berglund5, Kaan Boztug6, Anthony Lau1, Emma Gostick7, David A Price8, Michael O'Sullivan9, Isabelle Meyts10, Sharon Choo11, Paul Gray12, Steven M Holland13, Elissa K Deenick14, Gulbu Uzel13, Stuart G Tangye15. 1. Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Darlinghurst, Australia. 2. Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia. 3. Children's Hospital at Westmead, Westmead, Australia; CIRCA (Clinical Immunogenomics Consortia Australia), Sydney, Australia. 4. Children's Hospital at Westmead, Westmead, Australia; CIRCA (Clinical Immunogenomics Consortia Australia), Sydney, Australia; Discipline of Child and Adolescent Health, Faculty of Medicine, University of Sydney, Sydney, Australia. 5. CIRCA (Clinical Immunogenomics Consortia Australia), Sydney, Australia; Immunopathology Department, Westmead Hospital, Westmead, Australia; Faculty of Medicine, University of Sydney, Sydney, Australia. 6. 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. 7. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom. 8. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom; Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Md. 9. Perth Children's Hospital, Perth, Australia. 10. Department of Pediatrics, University Hospital Leuven, Leuven, Belgium; Department of Microbiology and Immunology, Childhood Immunology, KU Leuven, Leuven, Belgium. 11. Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia; Immunology Laboratory, Laboratory Services, Royal Children's Hospital, Melbourne, Australia. 12. CIRCA (Clinical Immunogenomics Consortia Australia), Sydney, Australia; University of New South Wales School of Women's and Children's Health, Randwick, Australia. 13. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 14. Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Darlinghurst, Australia; CIRCA (Clinical Immunogenomics Consortia Australia), Sydney, Australia. 15. Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Darlinghurst, Australia; CIRCA (Clinical Immunogenomics Consortia Australia), Sydney, Australia. Electronic address: s.tangye@garvan.org.au.
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.
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.
Authors: Stuart G Tangye; Julia Bier; Anthony Lau; Tina Nguyen; Gulbu Uzel; Elissa K Deenick Journal: J Clin Immunol Date: 2019-03-25 Impact factor: 8.317
Authors: Julia Bier; Geetha Rao; Kathryn Payne; Henry Brigden; Elise French; Simon J Pelham; Anthony Lau; Helen Lenthall; Emily S J Edwards; Joanne M Smart; Theresa S Cole; Sharon Choo; Avni Y Joshi; Roshini S Abraham; Michael O'Sullivan; Kaan Boztug; Isabelle Meyts; Paul E Gray; Lucinda J Berglund; Peter Hsu; Melanie Wong; Steven M Holland; Luigi D Notarangelo; Gulbu Uzel; Cindy S Ma; Robert Brink; Stuart G Tangye; Elissa K Deenick Journal: J Allergy Clin Immunol Date: 2019-02-06 Impact factor: 10.793
Authors: Bethany A Pillay; Danielle T Avery; Joanne M Smart; Theresa Cole; Sharon Choo; Damien Chan; Paul E Gray; Katie Frith; Richard Mitchell; Tri Giang Phan; Melanie Wong; Dianne E Campbell; Peter Hsu; John B Ziegler; Jane Peake; Frank Alvaro; Capucine Picard; Jacinta Bustamante; Benedicte Neven; Andrew J Cant; Gulbu Uzel; Peter D Arkwright; Jean-Laurent Casanova; Helen C Su; Alexandra F Freeman; Nirali Shah; Dennis D Hickstein; Stuart G Tangye; Cindy S Ma Journal: JCI Insight Date: 2019-04-25
Authors: Giorgia Bucciol; Leen Moens; Kathryn Payne; Elke Wollants; Djalila Mekahli; Elena Levtchenko; François Vermeulen; Thomas Tousseyn; Paul Gray; Cindy S Ma; Stuart G Tangye; Marc Van Ranst; Julianne R Brown; Judy Breuer; Isabelle Meyts Journal: J Clin Immunol Date: 2018-10-11 Impact factor: 8.317
Authors: Junghee J Shin; Jason Catanzaro; Jennifer R Yonkof; Ottavia Delmonte; Keith Sacco; Min Sun Shin; Srikar Reddy; Paula J Whittington; Gary Soffer; Peter J Mustillo; Kathleen E Sullivan; Luigi D Notarangelo; Roshini S Abraham; Neil Romberg; Insoo Kang Journal: J Clin Immunol Date: 2021-01-26 Impact factor: 8.317
Authors: Stephen A Schworer; Olivia L Francis; Steven M Johnson; Benjamin D Smith; Stuart H Gold; Andrew B Smitherman; Eveline Y Wu Journal: J Pediatr Hematol Oncol Date: 2021-11-01 Impact factor: 1.289