Senescent B cells regulate CD38 expression via FOXO1 in pneumonia resulting from PIK3CD (R437C) mutations

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Activated phosphoinositide 3-kinase delta syndrome (APDS) is a primary immunodeficiency.
• APDS is characterized by hyperactivated lymphocytes and recurrent infections.

Purpose of the Study:

• To investigate the immunological consequences of a novel PIK3CD gene mutation.
• To elucidate the molecular mechanisms underlying B-cell senescence and immune dysregulation in APDS.

Main Methods:

• Genetic analysis of a patient and mother with a novel PIK3CD mutation.
• Immunological assessment of T cell differentiation, B cell maturation, and mitochondrial function.
• Investigation of the PI3K/AKT/mTOR pathway and FOXO1 transcription factor activity.

Main Results:

• The novel PIK3CD mutation (c.1309C>T; p. R437C) caused defects in T and B cell development and mitochondrial function.
• Elevated CD38 expression on B cells was linked to senescence, mitochondrial dysfunction, and increased transitional B cells.
• The PI3K/AKT/mTOR pathway showed preferential mTORC2 activation, and FOXO1 regulated CD38 expression.

Conclusions:

• This novel mutation expands the known spectrum of PIK3CD mutations in APDS.
• FOXO1's role in regulating CD38 expression provides insight into B-cell dysfunction.
• Targeting the AKT-FOXO1 axis presents a potential therapeutic strategy for APDS.