Related Experiment Video
Updated: Feb 10, 2026
Radial Mobility and Cytotoxic Function of Retroviral Replicating Vector Transduced, Non-adherent Alloresponsive T Lymphocytes
Published on: February 11, 2015
Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity
Emily S J Edwards1, Julia Bier1, Theresa S Cole2
1Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Darlinghurst, Australia.
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.
Insights
Germline PIK3CD gain-of-function mutations impair T cell and NK cell immunity against EBV. These immune defects in PIK3CD GOF patients lead to increased susceptibility to infections and cancers.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Germline gain-of-function (GOF) mutations in PIK3CD cause a novel inborn error of immunity.
- These mutations lead to hyperactivation of the PI3K-AKT-mTOR pathway.
- Clinical manifestations include recurrent infections, autoimmunity, and increased risk of B-cell lymphoproliferation and lymphoma.
Purpose of the Study:
- To understand the mechanisms of inefficient surveillance of EBV-infected B cells in PIK3CD GOF patients.
- To identify key molecules involved in cell-mediated immunity against EBV.
- To inform the development of immunotherapeutic interventions for PIK3CD GOF and other EBV-related disorders.
Main Methods:
- Investigated the impact of PIK3CD GOF mutations on CD8+ T cell and natural killer (NK) cell generation, differentiation, and function.
- Utilized a novel mouse model recapitulating PI3K GOF mutations.
- Analyzed T cell and NK cell responses against Epstein-Barr virus (EBV).
Main Results:
- CD8+ T cells exhibited an effector phenotype with markers of premature immunosenescence/exhaustion and increased susceptibility to cell death.
- NK cells showed altered expression of differentiation markers.
- Both CD8+ T and NK cells demonstrated a reduced ability to eliminate EBV-infected B cells.
- PIK3CD GOF B cells displayed increased expression of CD48, PD-L1/2, and CD70.
Conclusions:
- PIK3CD GOF mutations induce aberrant T cell and NK cell exhaustion and senescence.
- Impaired cytotoxicity of CD8+ T and NK cells may contribute to clinical features like herpesvirus susceptibility and reduced tumor surveillance.
- These findings elucidate critical immune defects in PIK3CD GOF and suggest therapeutic targets.
Related Concept Videos
01:39Mutations
01:35Mutations
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
01:38What is the Immune System?
01:31Active versus Passive Immunity
Active Immunity
Active immunity refers to the resistance one develops...
01:28Functions of the Lymphatic and Immune System
The primary lymphoid organs, including the bone marrow and the thymus, serve as the maturation sites for lymphocytes. Secondary lymphoid organs, like the mucosa-associated lymphoid tissue, activate these lymphocytes and serve as...