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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
- 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.
- Subjects :
- Central Nervous System
Male
0301 basic medicine
Cell signaling
Cancer Research
Physiology
Signal transduction
Mouse models
T-Lymphocytes, Regulatory
White Blood Cells
Mice
Interleukin 21
0302 clinical medicine
Animal Cells
Immune Physiology
Medicine and Health Sciences
Cytotoxic T cell
IL-2 receptor
Genetics (clinical)
Staining
Innate Immune System
Thymocytes
TCR signaling cascade
Stem Cells
ZAP70
Signaling cascades
CD28
Forkhead Transcription Factors
Animal Models
Regulatory T cells
Natural killer T cell
Cell staining
3. Good health
Phenotype
medicine.anatomical_structure
Cytokines
[SDV.IMM]Life Sciences [q-bio]/Immunology
Female
Disease Susceptibility
Cellular Types
Research Article
Encephalomyelitis, Autoimmune, Experimental
Hematopoietic Progenitor Cells
lcsh:QH426-470
Immune Cells
T cell
Immunology
Receptors, Antigen, T-Cell
T cells
Thymus Gland
Biology
Research and Analysis Methods
03 medical and health sciences
T helper cells
Model Organisms
Genetics
medicine
Animals
Genetic Predisposition to Disease
Proto-Oncogene Proteins c-vav
Antigen-presenting cell
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Inflammation
Blood Cells
Polymorphism, Genetic
Biology and Life Sciences
Genetic Variation
Cell Biology
Molecular Development
Molecular biology
Rats
Mice, Inbred C57BL
lcsh:Genetics
030104 developmental biology
Specimen Preparation and Treatment
Immune System
Calcium
Developmental Biology
030215 immunology
Subjects
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⟩