| First Author | Takeda AJ | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 4364 |
| PubMed ID | 31554793 | Mgi Jnum | J:281173 |
| Mgi Id | MGI:6362137 | Doi | 10.1038/s41467-019-12311-5 |
| Citation | Takeda AJ, et al. (2019) Human PI3Kgamma deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology. Nat Commun 10(1):4364 |
| abstractText | Phosphatidylinositol 3-kinase-gamma (PI3Kgamma) 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 PI3Kgamma. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110gamma catalytic subunit of PI3Kgamma. 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. PI3Kgamma-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3alpha/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 PI3Kgamma in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice. |
