Signal strength controls the outcome of αβ T cell selection in the thymus, resulting in death if the affinity of the rearranged TCR is below the threshold for positive selection, or if the affinity of the TCR is above the threshold for negative selection. Here we show that deletion of the GTPase RRAS2 results in exacerbated negative selection and above-normal expression of positive selection markers. Furthermore, Rras2^−/− mice are resistant to autoimmunity both in a model of inflammatory bowel disease (IBD) and in a model of myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis (EAE). We show that MOG-specific T cells in Rras2^−/− mice have reduced affinity for MOG/I-A^b tetramers, suggesting that enhanced negative selection leads to selection of TCRs with lower affinity for the self-MOG peptide. An analysis of the TCR repertoire shows alterations that mostly affect the TCRα variable (TRAV) locus with specific VJ combinations and CDR3α sequences that are absent in Rras2^−/− mice, suggesting their involvement in autoimmunity.

信号强度控制着胸腺中αβT细胞选择的结果，如果重排的TCR的亲和力低于阳性选择的阈值，或者TCR的亲和力高于否定选择的阈值，则会导致死亡。在这里，我们显示GTPase RRAS2的缺失导致阴性选择加剧，阳性选择标记表达高于正常水平。此外，在炎症性肠病（IBD）模型和髓磷脂少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑脊髓炎（EAE）模型中，Rras2 ^-/-小鼠均对自身免疫具有抗性。我们显示，Rras2 ^-/-小鼠中的MOG特异性T细胞对MOG / IA ^b的亲和力降低四聚体，表明增强的阴性选择导致对自身MOG肽具有较低亲和力的TCR的选择。对TCR组成部分的分析显示，这种变化主要影响Rras2 ^-/-小鼠中不存在的特定VJ组合和CDR3α序列的TCRα变量（TRAV）基因座，表明它们参与了自身免疫。