Title |
Hyperactivated PI3Kδ promotes self and commensal reactivity at the expense of optimal humoral immunity
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Published in |
Nature Immunology, August 2018
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DOI | 10.1038/s41590-018-0182-3 |
Pubmed ID | |
Authors |
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. Notarangelo, Yasmine Belkaid, Ronald N. Germain, Pamela L. Schwartzberg |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 9 | 19% |
United Kingdom | 6 | 13% |
France | 2 | 4% |
Australia | 1 | 2% |
Spain | 1 | 2% |
India | 1 | 2% |
China | 1 | 2% |
Brazil | 1 | 2% |
Taiwan | 1 | 2% |
Other | 4 | 8% |
Unknown | 21 | 44% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 28 | 58% |
Scientists | 16 | 33% |
Science communicators (journalists, bloggers, editors) | 3 | 6% |
Practitioners (doctors, other healthcare professionals) | 1 | 2% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 129 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 30 | 23% |
Researcher | 29 | 22% |
Student > Doctoral Student | 10 | 8% |
Student > Bachelor | 9 | 7% |
Student > Master | 6 | 5% |
Other | 13 | 10% |
Unknown | 32 | 25% |
Readers by discipline | Count | As % |
---|---|---|
Immunology and Microbiology | 38 | 29% |
Biochemistry, Genetics and Molecular Biology | 18 | 14% |
Agricultural and Biological Sciences | 17 | 13% |
Medicine and Dentistry | 14 | 11% |
Nursing and Health Professions | 2 | 2% |
Other | 5 | 4% |
Unknown | 35 | 27% |