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Front Immunol. 2018 Oct 8;9:2311. doi: 10.3389/fimmu.2018.02311. eCollection 2018.

Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-b.

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Division of Translational Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.


Genome-wide association studies as well as lymphatic expression analyses have linked both Cbl-b and GM-CSF to human multiple sclerosis as well as other autoimmune diseases. Both Cbl-b and GM-CSF have been shown to play a prominent role in the development of murine encephalomyelitis; however, no functional connection between the two has yet been established. In this study, we show that Cblb knockout mice demonstrated significantly exacerbated severity of experimental autoimmune encephalomyelitis (EAE), augmented T cell infiltration into the central nervous system (CNS) and strongly increased production of GM-CSF in T cells in vitro and in vivo.GM-CSF neutralization demonstrated that the increased susceptibility of Cblb -/- mice to EAE was dependent on GM-CSF. Mechanistically, p50 binding to the GM-CSF promoter and the IL-3/GM-CSF enhancer element "CNSa" was strongly increased in nuclear extracts from Cbl-b-deficient T cells. This study suggests that Cbl-b limits autoimmunity by preventing the pathogenic effects of GM-CSF overproduction in T cells.


Cbl-b; GM-CSF; adaptive immunity; experimental autoimmune encephalomyelitis; multiple sclerosis

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