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

Silvia Preite, Jennifer L. Cannons, Andrea J. Radtke, Ivan Vujkovic-Cvijin, Julio Gomez-Rodriguez, Stefano Volpi, Bonnie Huang, Jun Cheng, Nicholas Collins, Julie Reilley, Robin Handon, Kerry Dobbs, Lutfi Huq, Indu Raman, Chengsong Zhu, Quan Zhen Li, Ming O. Li, Stefania Pittaluga, Gulbu Uzel, Luigi D. NotarangeloYasmine Belkaid, Ronald N. Germain, Pamela L. Schwartzberg

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)986-1000
Number of pages15
JournalNature Immunology
Volume19
Issue number9
DOIs
Publication statusPublished - Sep 1 2018

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Preite, S., Cannons, J. L., Radtke, A. J., Vujkovic-Cvijin, I., Gomez-Rodriguez, J., Volpi, S., Huang, B., Cheng, J., Collins, N., Reilley, J., Handon, R., Dobbs, K., Huq, L., Raman, I., Zhu, C., Li, Q. Z., Li, M. O., Pittaluga, S., Uzel, G., ... Schwartzberg, P. L. (2018). Hyperactivated PI3Kδ promotes self and commensal reactivity at the expense of optimal humoral immunity. Nature Immunology, 19(9), 986-1000. https://doi.org/10.1038/s41590-018-0182-3