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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.

Author information

1
Division of Translational Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
2
Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.
3
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.

Abstract

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.

KEYWORDS:

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

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