Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity
BACKGROUND: Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110delta 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.
|ISBN||1097-6825 (Electronic) 0091-6749 (Linking)|
|Authors||Edwards, E. S. J.; Bier, J.; Cole, T. S.; Wong, M.; Hsu, P.; Berglund, L. J.; Boztug, K.; Lau, A.; Gostick, E.; Price, D. A.; O'Sullivan, M.; Meyts, I.; Choo, S.; Gray, P.; Holland, S. M.; Deenick, E. K.; Uzel, G.; Tangye, S. G.|
|Responsible Garvan Author||Prof Stuart Tangye|
|Publisher Name||JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY|
|Published Pages||276-291 e6|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/29800648|