期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 143, 期 1, 页码 276-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2018.04.030
关键词
PIK3CD; CD8(+) T cells; memory; exhaustion/senescence; EBV
资金
- Susan and John Freeman Cancer Research Grant from Cancer Council NSW(Australia)
- Office of Health and Medical Research of the NSW Government
- Jeffrey Modell Foundation
- John Cook Brown Foundation
- National Health and Medical Research Council of Australia [1088215, 1127157]
- NHMRC [1042925]
- National Health and Medical Research Council of Australia [1088215, 1127157] Funding Source: NHMRC
Background: Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110 delta 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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