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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Autoimmunity / genetics
  • CD4-Positive T-Lymphocytes / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Gene Expression Regulation
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
  • Interleukin-3 / genetics
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-cbl / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cblb protein, mouse
  • Interleukin-3
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Proto-Oncogene Proteins c-cbl