Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology.

Autor: Takeda AJ; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA., Maher TJ; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA., Zhang Y; 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., Lanahan SM; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA., Bucklin ML; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA., Compton SR; Department of Comparative Medicine, Yale University, New Haven, CT, USA., Tyler PM; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA., Comrie WA; Clinical Genomics Program and Molecular Development of the Immune System Section, Laboratory of Immunology, NIAID, NIH, Bethesda, MD, USA., Matsuda M; Laboratory of Molecular Biology, Medical Research Council, Cambridge, UK., Olivier KN; Pulmonary Branch, Division of Intramural Research, NHLBI, NIH, Bethesda, MD, USA., Pittaluga S; Laboratory of Pathology, Clinical Center, NCI, NIH, Bethesda, MD, USA., McElwee JJ; Merck Research Laboratories, Merck & Co, Boston, MA, USA., Long Priel DA; Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Kuhns DB; Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Williams RL; Laboratory of Molecular Biology, Medical Research Council, Cambridge, UK., Mustillo PJ; Division of Infectious Diseases and Immunology, Nationwide Children's Hospital, Columbus, OH, USA., Wymann MP; University of Basel, Department of Biomedicine, Basel, Switzerland., Koneti Rao V; Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA., Lucas CL; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Carrie.Lucas@yale.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Sep 25; Vol. 10 (1), pp. 4364. Date of Electronic Publication: 2019 Sep 25.
DOI: 10.1038/s41467-019-12311-5
Abstrakt: 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.
Databáze: MEDLINE