title: E3 ubiquitin ligase Cbl-b suppresses proallergic T cell development and allergic airway inflammation.
abstract: E3 ubiquitin ligase Cbl-b has emerged as a gatekeeper that controls the activation threshold of the T cell antigen receptor and maintains the balance between tolerance and autoimmunity. Here, we report that the loss of Cbl-b facilitates T helper 2 (Th2) and Th9 cell differentiation in vitro. In a mouse model of asthma, the absence of Cbl-b results in severe airway inflammation and stronger Th2 and Th9 responses. Mechanistically, Cbl-b selectively associates with Stat6 upon IL-4 ligation and targets Stat6 for ubiquitination and degradation. These processes are heightened in the presence of T cell receptor (TCR)/CD28 costimulation. Furthermore, we identify K108 and K398 as Stat6 ubiquitination sites. Intriguingly, introducing Stat6 deficiency into Cblb(-/-) mice abrogates hyper-Th2 responses but only partially attenuates Th9 responses. Therefore, our data reveal a function for Cbl-b in the regulation of Th2 and Th9 cell differentiation.
authors: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA. Electronic address: glqiao@uic.edu.
authors: Guilin
authors: G
authors: Qiao
authors: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
authors: Haiyan
authors: H
authors: Ying
authors: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH 43210, USA; Department of Cardiology, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors: Yixia
authors: Y
authors: Zhao
authors: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH 43210, USA; Department of Cardiology, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors: Yanran
authors: Y
authors: Liang
authors: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH 43210, USA.
authors: Hui
authors: H
authors: Guo
authors: Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH 43210, USA.
authors: Huifeng
authors: H
authors: Shen
authors: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors: Zhenping
authors: Z
authors: Li
authors: Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, IL 60637, USA.
authors: Julian
authors: J
authors: Solway
authors: Department of Neurology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China.
authors: Enxiang
authors: E
authors: Tao
authors: Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Y Jeffrey
authors: YJ
authors: Chiang
authors: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Stanley
authors: S
authors: Lipkowitz
authors: Institute of Molecular Biotechnology, Austrian Academy of Sciences, 1030 Vienna, Austria.
authors: Josef M
authors: JM
authors: Penninger
authors: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA 6009, Australia.
authors: Wallace Y
authors: WY
authors: Langdon
authors: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH 43210, USA. Electronic address: jian.zhang@osumc.edu.
authors: Jian
authors: J
authors: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism*; D018106:CD28 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; C118387:Cblb protein, mouse; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D050721:Proto-Oncogene Proteins c-cbl