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, Debra A. Long Priel, Douglas B. Kuhns, Roger L. Williams, Peter J. Mustillo, Matthias P. Wymann, V. Koneti Rao and Carrie L. Lucas ()
Additional contact information
Andrew J. Takeda: Yale University School of Medicine
Timothy J. Maher: Yale University School of Medicine
Yu Zhang: Laboratory of Immunology, NIAID, NIH
Stephen M. Lanahan: Yale University School of Medicine
Molly L. Bucklin: Yale University School of Medicine
Susan R. Compton: Yale University
Paul M. Tyler: Yale University School of Medicine
William A. Comrie: Laboratory of Immunology, NIAID, NIH
Makoto Matsuda: Medical Research Council
Kenneth N. Olivier: Division of Intramural Research, NHLBI, NIH
Stefania Pittaluga: Clinical Center, NCI, NIH
Joshua J. McElwee: Merck Research Laboratories, Merck & Co
Debra A. Long Priel: Inc., Frederick National Laboratory for Cancer Research
Douglas B. Kuhns: Inc., Frederick National Laboratory for Cancer Research
Roger L. Williams: Medical Research Council
Peter J. Mustillo: Nationwide Children’s Hospital
Matthias P. Wymann: University of Basel, Department of Biomedicine
V. Koneti Rao: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Carrie L. Lucas: Yale University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12311-5

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