1. Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-b
- Author
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Peer, Sebastian, Cappellano, Giuseppe, Hermann-Kleiter, Natascha, Albrecht-Schgoer, Karin, Hinterleitner, Reinhard, Baier, Gottfried, and Gruber, Thomas
- Subjects
CD4-Positive T-Lymphocytes ,Mice, Knockout ,Encephalomyelitis, Autoimmune, Experimental ,Immunology ,experimental autoimmune encephalomyelitis ,Granulocyte-Macrophage Colony-Stimulating Factor ,GM-CSF ,Autoimmunity ,adaptive immunity ,multiple sclerosis ,Mice, Inbred C57BL ,Gene Expression Regulation ,Cbl-b ,Animals ,Interleukin-3 ,Proto-Oncogene Proteins c-cbl ,Promoter Regions, Genetic ,Original Research ,Adaptor Proteins, Signal Transducing - 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.
- Published
- 2018