Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology

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.