Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse, UPS, Inserm, CNRS, Toulouse, France.
Front Immunol. 2018 Oct 25;9:2399. doi: 10.3389/fimmu.2018.02399. eCollection 2018.
The guanine nucleotide exchange factor Vav1 is essential for transducing T cell receptor (TCR) signals and plays an important role in T cell development and activation. Previous genetic studies identified a natural variant of Vav1 characterized by the substitution of an arginine (R) residue by a tryptophane (W) at position 63 (Vav1). This variant impacts Vav1 adaptor functions and controls susceptibility to T cell-mediated neuroinflammation. To assess the implication of this Vav1 variant on the susceptibility to antibody-mediated diseases, we used the animal model of myasthenia gravis, experimental autoimmune myasthenia gravis (EAMG). To this end, we generated a knock-in (KI) mouse model bearing a R to W substitution in the Vav1 gene (Vav1) and immunized it with either torpedo acetylcholine receptor (tAChR) or the α146-162 immunodominant peptide. We observed that the Vav1 conferred increased susceptibility to EAMG, revealed by a higher AChR loss together with an increased production of effector cytokines (IFN-γ, IL-17A, GM-CSF) by antigen-specific CD4 T cells, as well as an increased frequency of antigen-specific CD4 T cells. This correlated with the emergence of a dominant antigen-specific T cell clone in KI mice that was not present in wild-type mice, suggesting an impact on thymic selection and/or a different clonal selection threshold following antigen encounter. Our results highlight the key role of Vav1 in the pathophysiology of EAMG and this was associated with an impact on the TCR repertoire of AChR reactive T lymphocytes.
鸟嘌呤核苷酸交换因子 Vav1 对于转导 T 细胞受体 (TCR) 信号至关重要，并且在 T 细胞发育和激活中发挥重要作用。先前的遗传研究鉴定了 Vav1 的一种天然变体，其特征在于第 63 位的精氨酸 (R) 残基被色氨酸 (W) 取代 (Vav1)。这种变体影响 Vav1 衔接子功能并控制 T 细胞介导的神经炎症易感性。为了评估这种 Vav1 变体对抗体介导疾病易感性的影响，我们使用重症肌无力的动物模型，实验性自身免疫性重症肌无力 (EAMG)。为此，我们生成了一种携带 Vav1 基因中 R 到 W 取代的敲入 (KI) 小鼠模型 (Vav1)，并用河豚乙酰胆碱受体 (tAChR) 或 α146-162 免疫优势肽对其进行免疫。我们观察到 Vav1 增加了 EAMG 的易感性，这表现为 AChR 丢失增加，以及抗原特异性 CD4 T 细胞产生效应细胞因子 (IFN-γ、IL-17A、GM-CSF) 增加，以及抗原特异性 CD4 T 细胞频率增加。这与 KI 小鼠中出现的主导抗原特异性 T 细胞克隆相关，而在野生型小鼠中不存在该克隆，这表明其对胸腺选择和/或抗原接触后不同的克隆选择阈值有影响。我们的结果强调了 Vav1 在 EAMG 病理生理学中的关键作用，这与 AChR 反应性 T 淋巴细胞 TCR 库的影响有关。
