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 R63W ). Using this model, we show that Vav1 R63W mice display reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by MOG 35-55 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 Vav1 R63W 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 R63W 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. 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 Vav1 R63W natural variant that has been supposed to play a central role in the susceptibility to neuroinflammation. Using a Vav1 R63W knock-in mouse model, we show that Vav1 R63W 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.
【초록키워드】 Cytokines, Diseases, T cells, GM-CSF, susceptibility, Genetic, variant, polymorphism, peptide, cytokine, immune system, immunization, Antigen, Polymorphisms, T cell, Regulatory T cell, mice, Neuroinflammation, Control, phenotype, Inflammatory cytokines, Autoimmune, receptor, T cell receptor, Quantitative, mechanism, regulatory T cells, FOXP3, cytokine production, function, Inflammatory cytokine, Treg, IFN-γ, MOG, Signaling, nucleotide, CD4 T cells, Non-synonymous, candidate gene, physiological, CD4 T cell, IL-17, leads, antigen receptor, Activation, locus, These data, alteration, functions, effector T cells, genetic study, guanine, normal enzymatic activity, Vav1, Affect, highlight, intrinsic, proportion, reduced, changes in, reduce, chromosome 9, effector T cell, Th1/Th17, transducing, 【제목키워드】 T cell, function, natural, molecule, effector,