Ulivieri Cristina, Savino Maria Teresa, Luccarini Ilaria, Fanigliulo Emanuela, Aldinucci Alessandra, Bonechi Elena, Benagiano Marisa, Ortensi Barbara, Pelicci Giuliana, D'Elios Mario Milco, Ballerini Clara, Baldari Cosima Tatiana
Department of Life Sciences, University of Siena, 2 53100, Siena, Italy;
Department of Neurosciences, 6 50134 Florence, Italy;
J Immunol. 2016 Jul 15;197(2):480-90. doi: 10.4049/jimmunol.1502063. Epub 2016 Jun 10.
Th17 cells have been casually associated to the pathogenesis of autoimmune disease. We have previously demonstrated that Rai/ShcC, a member of the Shc family of adaptor proteins, negatively regulates Th17 cell differentiation and lupus autoimmunity. In this study, we have investigated the pathogenic outcome of the Th17 bias associated with Rai deficiency on multiple sclerosis development, using the experimental autoimmune encephalomyelitis (EAE) mouse model. We found that, unexpectedly, EAE was less severe in Rai(-/-) mice compared with their wild-type counterparts despite an enhanced generation of myelin-specific Th17 cells that infiltrated into the CNS. Nevertheless, when adoptively transferred into immunodeficient Rai(+/+) mice, these cells promoted a more severe disease compared with wild-type encephalitogenic Th17 cells. This paradoxical phenotype was caused by a dampened inflammatory response of astrocytes, which were found to express Rai, to IL-17. The results provide evidence that Rai plays opposite roles in Th17 cell differentiation and astrocyte activation, with the latter dominant over the former in EAE, highlighting this adaptor as a potential novel target for the therapy of multiple sclerosis.
Th17细胞与自身免疫性疾病的发病机制存在偶然关联。我们之前已经证明，接头蛋白Shc家族成员Rai/ShcC对Th17细胞分化和狼疮自身免疫起负向调节作用。在本研究中，我们使用实验性自身免疫性脑脊髓炎（EAE）小鼠模型，研究了与Rai缺乏相关的Th17偏向对多发性硬化症发展的致病结果。我们发现，出乎意料的是，尽管浸润到中枢神经系统的髓鞘特异性Th17细胞生成增加，但与野生型对照相比，Rai(-/-)小鼠的EAE病情较轻。然而，当将这些细胞过继转移到免疫缺陷的Rai(+/+)小鼠中时，与野生型致脑炎Th17细胞相比，它们会引发更严重的疾病。这种矛盾的表型是由星形胶质细胞对IL-17的炎症反应减弱所致，而星形胶质细胞被发现表达Rai。这些结果提供了证据，表明Rai在Th17细胞分化和星形胶质细胞激活中发挥相反作用，在EAE中后者作用强于前者，突出了这种接头蛋白作为多发性硬化症治疗潜在新靶点的地位。
