University of Siena, Via Aldo Moro, Siena, Italy.
J Leukoc Biol. 2013 Apr;93(4):549-59. doi: 10.1189/jlb.0712331. Epub 2013 Jan 23.
Rai, a Shc adapter family member, acts as a negative regulator of antigen receptor signaling in T and B cells. Rai(-/-) mice develop lupus-like autoimmunity associated to the spontaneous activation of self-reactive lymphocytes. Here, we have addressed the potential role of Rai in the development of the proinflammatory Th1 and Th17 subsets, which are centrally implicated in the pathogenesis of a number of autoimmune diseases, including lupus. We show that Rai(-/-) mice display a spontaneous Th1/Th17 bias. In vitro polarization experiments on naive and effector/memory CD4(+) T cells demonstrate that Rai(-/-) favors the development and expansion of Th17 but not Th1 cells, indicating that Rai modulates TCR signaling to antagonize the pathways driving naive CD4(+) T cell differentiation to the Th17 lineage, while indirectly limiting Th1 cell development in vivo. Th1 and Th17 cell infiltrates were found in the kidneys of Rai(-/-) mice, providing evidence that Rai(-/-) contributes to the development of lupus nephritis, not only by enhancing lymphocyte activation but also by promoting the development and expansion of proinflammatory effector T cells. Interestingly, T cells from SLE patients were found to have a defect in Rai expression, suggesting a role for Rai in disease pathogenesis.
Rai 是 Shc 衔接蛋白家族的一员，在 T 和 B 细胞中作为抗原受体信号的负调节剂起作用。Rai(-/-) 小鼠会发展出类似于狼疮的自身免疫性疾病，与自身反应性淋巴细胞的自发性激活有关。在这里，我们研究了 Rai 在促炎性 Th1 和 Th17 亚群发育中的潜在作用，这些亚群与许多自身免疫性疾病的发病机制密切相关，包括狼疮。我们发现 Rai(-/-) 小鼠表现出自发的 Th1/Th17 偏向。在幼稚和效应/记忆 CD4(+) T 细胞上进行的体外极化实验表明，Rai(-/-) 有利于 Th17 的发育和扩增，而不是 Th1 细胞，这表明 Rai 调节 TCR 信号以拮抗驱动幼稚 CD4(+) T 细胞向 Th17 谱系分化的途径，同时在体内间接限制 Th1 细胞的发育。在 Rai(-/-) 小鼠的肾脏中发现了 Th1 和 Th17 细胞浸润，这为 Rai(-/-) 不仅通过增强淋巴细胞激活而且通过促进促炎性效应 T 细胞的发育和扩增来促进狼疮肾炎的发展提供了证据。有趣的是，发现来自 SLE 患者的 T 细胞存在 Rai 表达缺陷，这表明 Rai 在疾病发病机制中起作用。
