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A Natural Variant of the T Cell Receptor-Signaling Molecule Vav1 Reduces Both Effector T Cell Functions and Susceptibility to Neuroinflammation.
- Source :
- PLoS Genetics; 7/20/2016, Vol. 12 Issue 7, p1-17, 17p
- Publication Year :
- 2016
-
Abstract
- The guanine nucleotide exchange factor Vav1 is essential for transducing T cell antigen receptor signals and therefore plays an important role in T cell development and activation. Our previous genetic studies identified a locus on rat chromosome 9 that controls the susceptibility to neuroinflammation and contains a non-synonymous polymorphism in the major candidate gene Vav1. To formally demonstrate the causal implication of this polymorphism, we generated a knock-in mouse bearing this polymorphism (Vav1<superscript>R63W</superscript>). Using this model, we show that Vav1<superscript>R63W</superscript> mice display reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by MOG<subscript>35-55</subscript> peptide immunization. This is associated with a lower production of effector cytokines (IFN-γ, IL-17 and GM-CSF) by autoreactive CD4 T cells. Despite increased proportion of Foxp3+ regulatory T cells in Vav1<superscript>R63W</superscript> mice, we show that this lowered cytokine production is intrinsic to effector CD4 T cells and that Treg depletion has no impact on EAE development. Finally, we provide a mechanism for the above phenotype by showing that the Vav1<superscript>R63W</superscript> variant has normal enzymatic activity but reduced adaptor functions. Together, these data highlight the importance of Vav1 adaptor functions in the production of inflammatory cytokines by effector T cells and in the susceptibility to neuroinflammation. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15537390
- Volume :
- 12
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- PLoS Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 116909770
- Full Text :
- https://doi.org/10.1371/journal.pgen.1006185