Activated PIK3CD drives marginal zone B cell development from early transitional progenitors by enhancing ADAM10...

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Activated PI3K-delta syndrome (APDS) is a primary immunodeficiency caused by PIK3CD mutations.
• APDS presents with immune dysregulation, including infections and autoimmunity.
• Impaired B cell development, particularly marginal zone B cells, is implicated in APDS pathogenesis.

Purpose of the Study:

• To investigate the role of PI3Kδ signaling in spleen marginal zone B cell development using a mouse model of APDS.

Main Methods:

• Utilized a mouse model of activated PI3Kδ syndrome.
• Employed single-cell RNA sequencing (scRNA-seq) to analyze B cell differentiation.
• Investigated the effect of an ADAM10 inhibitor on B cell development.

Main Results:

• Hyperactive PI3Kδ signaling increases spleen marginal zone B cell precursors with elevated ADAM10 levels at the T1 stage.
• scRNA-seq revealed divergent cell differentiation at the T1 stage.
• ADAM10 inhibition suppressed marginal zone B cell differentiation and partially corrected T1/T2 stage imbalance.

Conclusions:

• Findings elucidate mechanisms of imbalanced marginal zone B cell development in APDS.
• Provides a basis for developing strategies to target autoimmune B cells in APDS.