title: A Natural Variant of the T Cell Receptor-Signaling Molecule Vav1 Reduces Both Effector T Cell Functions and Susceptibility to Neuroinflammation.
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.
authors.affiliation: UMR Inserm, U1043, Toulouse, France.|UMR CNRS, U5282, Toulouse, France.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors.forename: Sahar
authors.initials: S
authors.lastname: Kassem
authors.affiliation: UMR Inserm, U1043, Toulouse, France.|UMR CNRS, U5282, Toulouse, France.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors.forename: Guillaume
authors.identifier: 0000-0001-8415-854X
authors.initials: G
authors.lastname: Gaud
authors.affiliation: UMR Inserm, U1043, Toulouse, France.|UMR CNRS, U5282, Toulouse, France.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bernard
authors.affiliation: UMR Inserm, U1043, Toulouse, France.|UMR CNRS, U5282, Toulouse, France.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors.forename: Mehdi
authors.identifier: 0000-0003-1532-8642
authors.initials: M
authors.lastname: Benamar
authors.affiliation: UMR Inserm, U1043, Toulouse, France.|UMR CNRS, U5282, Toulouse, France.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Dejean
authors.affiliation: UMR Inserm, U1043, Toulouse, France.|UMR CNRS, U5282, Toulouse, France.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Liblau
authors.affiliation: UMR Inserm, U1043, Toulouse, France.|UMR CNRS, U5282, Toulouse, France.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Fournié
authors.affiliation: UMR Inserm, U1043, Toulouse, France.|UMR CNRS, U5282, Toulouse, France.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Colacios
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, Marseille, France.|Centre d'Immunophénomique, Aix Marseille Université UM2, Inserm US012, CNRS UMS3367, 13288 Marseille, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.affiliation: UMR Inserm, U1043, Toulouse, France.|UMR CNRS, U5282, Toulouse, France.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors.forename: Abdelhadi
authors.initials: A
authors.lastname: Saoudi
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002490:Central Nervous System / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D004198:Disease Susceptibility; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011110:Polymorphism, Genetic; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics*; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D013950:Thymus Gland / Q000378:metabolism
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse; D002118:Calcium