We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology.
- Authors
Takeda, Andrew J.; Maher, Timothy J.; Zhang, Yu; Lanahan, Stephen M.; Bucklin, Molly L.; Compton, Susan R.; Tyler, Paul M.; Comrie, William A.; Matsuda, Makoto; Olivier, Kenneth N.; Pittaluga, Stefania; McElwee, Joshua J.; Long Priel, Debra A.; Kuhns, Douglas B.; Williams, Roger L.; Mustillo, Peter J.; Wymann, Matthias P.; Koneti Rao, V.; Lucas, Carrie L.
- 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. Causally linking a mutation to clinical phenotypes in rare hereditary diseases is both challenging and illuminating. Here the authors identify PI3Kɣ mutations in a patient with immune dysregulation, and recapitulate the phenotypes in PI3Kɣ-deficient mice by exposing them to natural microbiota from pet-shop mice.
- Subjects
SUPPRESSOR cells; T cells; IMMUNOREGULATION; GENETIC disorders
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-12311-5