Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Allergy, Immunology, PIK3CD, CD8(+) T cells, memory, exhaustion/senescence, EBV, T-CELL EXHAUSTION, 3-KINASE DELTA SYNDROME, NATURAL-KILLER-CELLS, PHOSPHOINOSITIDE 3-KINASE, B-CELL, P110 DELTA, EXPRESSION, PI3K-DELTA, INFECTION, SURVIVAL, Adolescent, Adult, Aged, B-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Differentiation, Cellular Senescence, Child, Child, Preschool, Class I Phosphatidylinositol 3-Kinases, Epstein-Barr Virus Infections, Gain of Function Mutation, Genetic Diseases, Inborn, Herpesvirus 4, Human, Humans, Immunologic Surveillance, Killer Cells, Natural, Male, Middle Aged, 1107 Immunology, 3204 Immunology

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.