Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-12311-5
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Funding
- Hood Foundation
- Immune Deficiency Foundation
- NIAID [5T32AI007019]
- Yale University
- Division of Intramural Research at the National Institute of Allergy and Infectious Diseases
- National Institutes of Health (NIH) Clinical Center
- National Heart, Lung and Blood Institute NIH
- Merck Inc.
- British Heart Foundation [PG11/109/2924]
- Medical Research Council [MC_U105184308]
- MRC [MC_U105184308] Funding Source: UKRI
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Phosphatidylinositol 3-kinase-gamma (PI3K gamma) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3K gamma. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110 gamma catalytic subunit of PI3K gamma. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3K gamma-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3 alpha/beta-dependent manner upon TLR stimulation. Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3K gamma in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.
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