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

backgroundActivated PI3K-delta syndrome (APDS) is a human monogenic primary immunodeficiency disorder caused by mutations in the gene encoding the p110δ catalytic subunit of phosphoinositide 3-kinase, PIK3CD. APDS is characterized by complex immune phenotypes, including increased serum IgM, susceptibility to encapsulated bacterial respiratory infections, poor vaccine response, and autoimmune disorders. Impaired B cell development and responses, involving an expansion at the transient transitional T1 stage and a strikingly selective expansion of autoreactive marginal zone B cells, may be largely responsible for these phenotypes, although little is known about the precise underlying mechanisms.

methodsIn this study, we used a mouse model of activated PI3Kδ syndrome to investigate the role of altered PI3Kδ signaling specifically within the spleen marginal zone B cell development.

resultsHere, we report that hyperactive P110δ leads to an increase in the proportion of spleen marginal zone B cell precursors with enhanced surface ADAM10 levels, as early as the T1 stage of B cell development. Using single-cell RNA sequencing (scRNA-seq), we also identified divergent cell differentiation at the T1 stage. The ADAM10 inhibitor suppresses marginal zone B cells differentiation and also partially reverses the imbalance of transitional T1 and T2 stage.

conclusionThese findings inform understanding of the mechanism underlying imbalanced marginal zone B cell development in APDS from a shallow perspective, and provide a preliminary platform for future investigation of strategies to target autoimmune B cells in this disease.