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Human PI3Kγ Deficiency and Its Microbiota-Dependent Mouse Model Reveal Immunodeficiency and Tissue Immunopathology

Human PI3Kγ Deficiency and Its Microbiota-Dependent Mouse Model Reveal Immunodeficiency and Tissue Immunopathology

Andrew J Takeda, Timothy J Maher, Yu Zhang, Stephen M Lanahan, Molly L Bucklin, Susan R Compton, Paul M Tyler, William A Comrie, Makoto Matsuda, Kenneth N Olivier, Stefania Pittaluga, Joshua J McElwee, etc.

Nat Commun. 2019 Sep 25;10(1):4364.

PMID: 31554793

Abstract:

Phosphatidylinositol 3-kinase-gamma (PI3Kγ) 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 PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. 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. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/β-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 PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4247094	Phosphoinositide 3-kinase p110γ human			Price

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