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Hyperactivated PI3K? promotes self and commensal reactivity at the expense of optimal humoral immunity.

ABSTRACT: Gain-of-function mutations in the gene encoding the phosphatidylinositol-3-OH kinase catalytic subunit p110? (PI3K?) 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 PI3K? fosters aberrant humoral immunity. We found that mutant PI3K? 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 PI3K? is critical for ensuring optimal host-protective humoral immunity despite tonic stimulation from the commensal microbiome.

SUBMITTER: Preite S

PROVIDER: S-EPMC6140795 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Preite Silvia S Cannons Jennifer L JL Radtke Andrea J AJ Vujkovic-Cvijin Ivan I Gomez-Rodriguez Julio J Volpi Stefano S Huang Bonnie B Cheng Jun J Collins Nicholas N Reilley Julie J Handon Robin R Dobbs Kerry K Huq Lutfi L Raman Indu I Zhu Chengsong C Li Quan-Zhen QZ Li Ming O MO Pittaluga Stefania S Uzel Gulbu G Notarangelo Luigi D LD Belkaid Yasmine Y Germain Ronald N RN Schwartzberg Pamela L PL

Nature immunology 20180820 9

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 h ...[more]

PMID: 30127432

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Hyperactivated PI3K? promotes self and commensal reactivity at the expense of optimal humoral immunity.

Publications

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

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