2. Academic Validation
  3. 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

  • Nat Commun. 2019 Sep 25;10(1):4364. doi: 10.1038/s41467-019-12311-5.
Andrew J Takeda 1,  Timothy J Maher 1,  Yu Zhang 2 3,  Stephen M Lanahan 1,  Molly L Bucklin 1,  Susan R Compton 4,  Paul M Tyler 1,  William A Comrie 2,  Makoto Matsuda 5,  Kenneth N Olivier 6,  Stefania Pittaluga 7,  Joshua J McElwee 8,  Debra A Long Priel 9,  Douglas B Kuhns 9,  Roger L Williams 5,  Peter J Mustillo 10,  Matthias P Wymann 11,  V Koneti Rao 3,  Carrie L Lucas 12
Affiliations

Affiliations

  • 1 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
  • 2 Clinical Genomics Program and Molecular Development of the Immune System Section, Laboratory of Immunology, NIAID, NIH, Bethesda, MD, USA.
  • 3 Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.
  • 4 Department of Comparative Medicine, Yale University, New Haven, CT, USA.
  • 5 Laboratory of Molecular Biology, Medical Research Council, Cambridge, UK.
  • 6 Pulmonary Branch, Division of Intramural Research, NHLBI, NIH, Bethesda, MD, USA.
  • 7 Laboratory of Pathology, Clinical Center, NCI, NIH, Bethesda, MD, USA.
  • 8 Merck Research Laboratories, Merck & Co, Boston, MA, USA.
  • 9 Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 10 Division of Infectious Diseases and Immunology, Nationwide Children's Hospital, Columbus, OH, USA.
  • 11 University of Basel, Department of Biomedicine, Basel, Switzerland.
  • 12 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Carrie.Lucas@yale.edu.
PMID: 31554793 DOI: 10.1038/s41467-019-12311-5
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.

Figures
Products