TY - JOUR
T1 - Hyperactivated PI3Kδ promotes self and commensal reactivity at the expense of optimal humoral immunity
AU - Preite, Silvia
AU - Cannons, Jennifer L.
AU - Radtke, Andrea J.
AU - Vujkovic-Cvijin, Ivan
AU - Gomez-Rodriguez, Julio
AU - Volpi, Stefano
AU - Huang, Bonnie
AU - Cheng, Jun
AU - Collins, Nicholas
AU - Reilley, Julie
AU - Handon, Robin
AU - Dobbs, Kerry
AU - Huq, Lutfi
AU - Raman, Indu
AU - Zhu, Chengsong
AU - Li, Quan Zhen
AU - Li, Ming O.
AU - Pittaluga, Stefania
AU - Uzel, Gulbu
AU - Notarangelo, Luigi D.
AU - Belkaid, Yasmine
AU - Germain, Ronald N.
AU - Schwartzberg, Pamela L.
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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 (T FH 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.
AB - 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 (T FH 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.
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U2 - 10.1038/s41590-018-0182-3
DO - 10.1038/s41590-018-0182-3
M3 - Article
C2 - 30127432
AN - SCOPUS:85051995786
SN - 1529-2908
VL - 19
SP - 986
EP - 1000
JO - Nature immunology
JF - Nature immunology
IS - 9
ER -