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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Central Nervous System / physiopathology
  • Cytokines / metabolism
  • Disease Susceptibility
  • Encephalomyelitis, Autoimmune, Experimental / genetics*
  • Female
  • Forkhead Transcription Factors / metabolism
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Inflammation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • Polymorphism, Genetic
  • Proto-Oncogene Proteins c-vav / genetics*
  • Rats
  • Receptors, Antigen, T-Cell / genetics*
  • Signal Transduction
  • T-Lymphocytes, Regulatory / cytology*
  • Thymus Gland / metabolism

Substances

  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Proto-Oncogene Proteins c-vav
  • Receptors, Antigen, T-Cell
  • Vav1 protein, mouse
  • Calcium

Grant support

This work was supported by INSERM, Association Française contre les Myopathies, Agence Nationale de la Recherche (ANR-08-GENO-041-01), Fondation pour la Recherche Médicale (DEQ2000326531), Association de Recherche sur la Sclérose En Plaques, Région Midi-Pyrénées and Fight-MG (FP7-Health-2009-242210). AS and BM are supported by Centre National de la Recherche Scientifique, GJF, IB and ASD by INSERM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.