Genetic Defects in Phosphoinositide 3-Kinase δ Influence CD8⁺ T Cell Survival, Differentiation, and Function

Area of Science:

• Immunology
• Genetics
• Virology

Background:

• Activated phosphoinositide 3-kinase delta syndrome (APDS), or PASLI, is an autosomal dominant primary immunodeficiency (PID). It stems from gain-of-function mutations in PIK3CD, encoding the p110δ subunit of PI3K.
• APDS presents with varied clinical features, including recurrent infections, lymphoproliferation, lymphopenia, and poor antibody responses.
• Chronic Epstein-Barr virus (EBV) and/or cytomegalovirus viremia are significant manifestations in APDS patients, even with normal or elevated EBV-specific CD8+ T cell counts.

Purpose of the Study:

• To investigate the functional defects of CD8+ T cells in APDS/PASLI patients.
• To understand how these T cell defects contribute to the inability to clear chronic viral infections, particularly EBV.
• To provide insights into potential cellular mechanisms underlying persistent infections in APDS.

Main Methods:

• Review of existing data on CD8+ T cell function in APDS/PASLI patients.
• Analysis of T cell death, exhaustion markers, and cytotoxic activity against EBV-infected cells.
• Examination of PI3K pathway signaling in relation to cellular defects.

Main Results:

• APDS patients exhibit increased CD8+ T cell death and elevated expression of exhaustion markers.
• Impaired killing of autologous EBV-infected B cells by CD8+ T cells was observed.
• Functional T cell deficits, rather than frequency, appear critical in persistent viral infections.

Conclusions:

• Dysfunctional CD8+ T cells, characterized by increased apoptosis and exhaustion, are a key feature of APDS.
• These cellular defects hinder the clearance of chronic viral infections like EBV.
• Targeting PI3K signaling may offer therapeutic strategies for improving T cell function and managing infections in APDS.