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DOI | 10.1038/ncomms16020 |
Human PI3K gamma deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology | |
Takeda, Andrew J.1; Maher, Timothy J.1; Zhang, Yu2,3,4; Lanahan, Stephen M.1; Bucklin, Molly L.1; Compton, Susan R.5; Tyler, Paul M.1; Comrie, William A.2,3; Matsuda, Makoto6; Olivier, Kenneth N.7; Pittaluga, Stefania8; McElwee, Joshua J.9; Priel, Debra A. Long10; Kuhns, Douglas B.10; Williams, Roger L.6; Mustillo, Peter J.11; Wymann, Matthias P.12; Rao, V. Koneti4; Lucas, Carrie L.1 | |
2019-09-25 | |
发表期刊 | NATURE COMMUNICATIONS |
ISSN | 2041-1723 |
出版年 | 2019 |
卷号 | 10 |
文章类型 | Article |
语种 | 英语 |
国家 | USA; England; Switzerland |
英文摘要 | 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. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000487585600025 |
WOS关键词 | PHOSPHOINOSITIDE 3-KINASE GAMMA ; T-CELL-ACTIVATION ; IMMUNE DYSREGULATION ; BETA-SELECTION ; DELTA SYNDROME ; INHIBITOR ; MUTATIONS ; RECEPTOR ; SUPPRESSION ; PI3K-DELTA |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/203374 |
专题 | 资源环境科学 |
作者单位 | 1.Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA; 2.NIAID, Clin Genom Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA; 3.NIAID, Mol Dev Immune Syst Sect, Lab Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA; 4.NIAID, Human Immunol Dis Sect, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA; 5.Yale Univ, Dept Comparat Med, New Haven, CT USA; 6.MRC, Lab Mol Biol, Cambridge, England; 7.NHLBI, Pulm Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA; 8.NCI, Lab Pathol, Clin Ctr, NIH, Bethesda, MD 20892 USA; 9.Merck & Co Inc, Merck Res Labs, Boston, MA USA; 10.Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Neutrophil Monitoring Lab, Applied Dev Res Directorate, Frederick, MD USA; 11.Nationwide Childrens Hosp, Div Infect Dis & Immunol, Columbus, OH USA; 12.Univ Basel, Dept Biomed, Basel, Switzerland |
推荐引用方式 GB/T 7714 | Takeda, Andrew J.,Maher, Timothy J.,Zhang, Yu,et al. Human PI3K gamma deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology[J]. NATURE COMMUNICATIONS,2019,10. |
APA | Takeda, Andrew J..,Maher, Timothy J..,Zhang, Yu.,Lanahan, Stephen M..,Bucklin, Molly L..,...&Lucas, Carrie L..(2019).Human PI3K gamma deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology.NATURE COMMUNICATIONS,10. |
MLA | Takeda, Andrew J.,et al."Human PI3K gamma deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology".NATURE COMMUNICATIONS 10(2019). |
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