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PLoS Genet. 2016 Jul 20;12(7):e1006185. doi: 10.1371/journal.pgen.1006185. eCollection 2016 Jul.

A Natural Variant of the T Cell Receptor-Signaling Molecule Vav1 Reduces Both Effector T Cell Functions and Susceptibility to Neuroinflammation.

Kassem S1,2,3, Gaud G1,2,3, Bernard I1,2,3, Benamar M1,2,3, Dejean AS1,2,3, Liblau R1,2,3, Fournié GJ1,2,3, Colacios C1,2,3, Malissen B4,5, Saoudi A1,2,3.

Author information

1
UMR Inserm, U1043, Toulouse, France.
2
UMR CNRS, U5282, Toulouse, France.
3
Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
4
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, Marseille, France.
5
Centre d'Immunophénomique, Aix Marseille Université UM2, Inserm US012, CNRS UMS3367, 13288 Marseille, France.

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 (Vav1R63W). Using this model, we show that Vav1R63W mice display reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 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 Vav1R63W 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 Vav1R63W 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.

PMID:
27438086
PMCID:
PMC4954684
DOI:
10.1371/journal.pgen.1006185
[Indexed for MEDLINE]
Free PMC Article

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