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
  • 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. [email protected].
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.

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