Hyperactivated PI3Kδ promotes self and commensal reactivity at the expense of optimal humoral immunity.
Silvia PreiteJennifer L CannonsAndrea J RadtkeIvan Vujkovic-CvijinJulio Gomez-RodriguezStefano VolpiBonnie HuangJun ChengNicholas CollinsJulie ReilleyRobin HandonA Kerry DobbsLutfi HuqIndu RamanChengsong ZhuQuan-Zhen LiMing O LiStefania PittalugaGulbu UzelLuigi Daniele NotarangeloYasmine BelkaidRonald N GermainPamela L SchwartzbergPublished in: Nature immunology (2018)
Gain-of-function mutations in the gene encoding the phosphatidylinositol-3-OH kinase catalytic subunit p110δ (PI3Kδ) result in a human primary immunodeficiency characterized by lymphoproliferation, respiratory infections and inefficient responses to vaccines. However, what promotes these immunological disturbances at the cellular and molecular level remains unknown. We generated a mouse model that recapitulated major features of this disease and used this model and patient samples to probe how hyperactive PI3Kδ fosters aberrant humoral immunity. We found that mutant PI3Kδ led to co-stimulatory receptor ICOS-independent increases in the abundance of follicular helper T cells (TFH cells) and germinal-center (GC) B cells, disorganized GCs and poor class-switched antigen-specific responses to immunization, associated with altered regulation of the transcription factor FOXO1 and pro-apoptotic and anti-apoptotic members of the BCL-2 family. Notably, aberrant responses were accompanied by increased reactivity to gut bacteria and a broad increase in autoantibodies that were dependent on stimulation by commensal microbes. Our findings suggest that proper regulation of PI3Kδ is critical for ensuring optimal host-protective humoral immunity despite tonic stimulation from the commensal microbiome.
Keyphrases
- immune response
- transcription factor
- cell death
- mouse model
- anti inflammatory
- protein kinase
- endothelial cells
- induced apoptosis
- cell cycle arrest
- systemic lupus erythematosus
- signaling pathway
- dendritic cells
- case report
- genome wide identification
- copy number
- gene expression
- tyrosine kinase
- endoplasmic reticulum stress
- wastewater treatment
- cell proliferation
- mass spectrometry
- microbial community