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Human PI3K gamma deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology

  1. Author:
    Takeda, Andrew J [ORCID]
    Maher, Timothy J
    Zhang, Yu
    Lanahan, Stephen M [ORCID]
    Bucklin, Molly L [ORCID]
    Compton, Susan R [ORCID]
    Tyler, Paul M
    Comrie, William A
    Matsuda, Makoto
    Olivier, Kenneth N
    Pittaluga, Stefania
    McElwee, Joshua J
    Long-Priel,Debra [ORCID]
    Kuhns,Doug
    Williams, Roger L [ORCID]
    Mustillo, Peter J
    Wymann, Matthias P [ORCID]
    Koneti Rao, V [ORCID]
    Lucas, Carrie L [ORCID]

  2. Author Address

    Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA., Clinical Genomics Program and Molecular Development of the Immune System Section, Laboratory of Immunology, NIAID, NIH, Bethesda, MD, USA., Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA., Department of Comparative Medicine, Yale University, New Haven, CT, USA., Laboratory of Molecular Biology, Medical Research Council, Cambridge, UK., Pulmonary Branch, Division of Intramural Research, NHLBI, NIH, Bethesda, MD, USA., Laboratory of Pathology, Clinical Center, NCI, NIH, Bethesda, MD, USA., Merck Research Laboratories, Merck & Co, Boston, MA, USA., Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Division of Infectious Diseases and Immunology, Nationwide Children 39;s Hospital, Columbus, OH, USA., University of Basel, Department of Biomedicine, Basel, Switzerland., Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Carrie.Lucas@yale.edu.,
    1. Year: 2019
    2. Date: Sep 25
    3. Epub Date: 2019 09 25
  2. Journal: Nature communications
    1. 10
    2. 1
    3. Pages: 4364
  4. Type of Article: Article
  5. Article Number: 4364
  6. ISSN: 2041-1723
  1. Abstract:

    Phosphatidylinositol 3-kinase-gamma (PI3K gamma) 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 PI3K gamma. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110 gamma catalytic subunit of PI3K gamma. 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. PI3K gamma-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3 alpha/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 PI3K gamma in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.

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External Sources

  1. View Full Text
  2. DOI: 10.1038/s41467-019-12311-5
  3. PMID: 31554793
  4. PMCID: PMC6761123
  5. View record in Web of Science®
  6. WOS: 000487585600025
  7. PII : 10.1038/s41467-019-12311-5

Library Notes

  1. Fiscal Year: FY2019-2020
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