Hyperactivated PI3Kδ promotes self and commensal reactivity at the expense of optimal humoral immunity

Gain-of-function mutations in phosphoinositide 3-kinase p110δ (PI3Kδ) result in a human primary immunodeficiency characterized by lymphoproliferation, respiratory infections and inefficient vaccine responses. However, what promotes these immune disturbances at the cellular and molecular level remains unknown. We describe a mouse model that recapitulates major features of this disease and use this model and patient samples to probe how hyperactive PI3Kδ fosters aberrant humoral immunity. We found that mutant PI3Kδ led to ICOS-independent increases in T follicular helper (T(FH)) and germinal center (GC) B cells, disorganized GCs, and poor class-switched antigen-specific responses to immunization, associated with altered regulation of FOXO1 and BCL-2 family members. Notably, aberrant responses were accompanied by increased reactivity to gut bacteria, and a broad increase in autoantibodies that were dependent on commensal microbial stimulation. Our findings suggest that proper PI3Kδ regulation is critical for ensuring optimal host-protective humoral immunity despite tonic stimulation from the commensal microbiome.