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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

Authors :
Isabelle Bernard
Céline Colacios
Abdelhadi Saoudi
Bernard Malissen
Anne Dejean
Mehdi Benamar
Sahar Kassem
Roland S. Liblau
Gilbert J. Fournié
Guillaume Gaud
Centre de Physiopathologie Toulouse Purpan (CPTP)
Université Toulouse III - Paul Sabatier (UT3)
Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Centre d'Immunologie de Marseille - Luminy (CIML)
Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
ANR-08-GENO-0041,VAV1GENOPAT,VAV1: un noeud de signalisation contrôlant l'homéostasie du système immunitaire et les maladies immunes(2008)
Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Source :
PLoS Genetics, PLoS Genetics, Public Library of Science, 2016, 12 (7), ⟨10.1371/journal.pgen.1006185⟩, PLoS Genetics, Vol 12, Iss 7, p e1006185 (2016), PLoS Genetics, 2016, 12 (7), ⟨10.1371/journal.pgen.1006185⟩
Publication Year :
2016
Publisher :
HAL CCSD, 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 (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.<br />Author Summary The understanding of the physiological role of Vav1, a key regulator of T cell receptor signaling, was primarily inferred from studies using Vav1-deficient mice. Such models, however, provide little insight on how polymorphisms leading to quantitative changes in Vav1 activity could affect immune system functions. In the present study, we focused on a recently identified Vav1R63W natural variant that has been supposed to play a central role in the susceptibility to neuroinflammation. Using a Vav1R63W knock-in mouse model, we show that Vav1R63W leads to defects in adaptor functions and reduces the susceptibility to experimental autoimmune encephalomyelitis, together with an intrinsic defect in the production of Th1/Th17 cytokines by autoreactive effector CD4 T cells. Thus, our study highlights the importance of Vav1 adaptor functions in CD4 T cells differentiation and suggests that genetic or acquired alterations of this Vav1 function could play a major role in susceptibility to Th1/Th17 mediated diseases.

Details

Language :
English
ISSN :
15537390 and 15537404
Database :
OpenAIRE
Journal :
PLoS Genetics, PLoS Genetics, Public Library of Science, 2016, 12 (7), ⟨10.1371/journal.pgen.1006185⟩, PLoS Genetics, Vol 12, Iss 7, p e1006185 (2016), PLoS Genetics, 2016, 12 (7), ⟨10.1371/journal.pgen.1006185⟩
Accession number :
edsair.doi.dedup.....c74df8f2dfe2601c2467ec4068ab2114
Full Text :
https://doi.org/10.1371/journal.pgen.1006185⟩