Rai (ShcC) belongs to the family of Shc adaptor proteins and is expressed in neuronal cells, where it acts as a survival factor activating the PI3K/Akt survival pathway. In vivo, Rai protects the brain from ischemic damage. In this study, we show that Rai is expressed in T and B lymphocytes. Based on the finding that Rai(-/-) mice consistently develop splenomegaly, the role of Rai in lymphocyte homeostasis and proliferation was addressed. Surprisingly, as opposed to neurons, Rai was found to impair lymphocyte survival. Furthermore, Rai deficiency results in a reduction in the frequency of peripheral T cells with a concomitant increase in the frequency of B cells. Rai(-/-) lymphocytes display enhanced proliferative responses to Ag receptor engagement in vitro, which correlates with enhanced signaling by the TCR and BCR, and more robust responses to allergen sensitization in vivo. A high proportion of Rai(-/-) mice develop a lupus-like autoimmune syndrome characterized by splenomegaly, spontaneous peripheral T and B cell activation, autoantibody production, and deposition of immune complexes in the kidney glomeruli, resulting in autoimmune glomerulonephritis. The data identify Rai as a negative regulator of lymphocyte survival and activation and show that loss of this protein results in breaking of immunological tolerance and development of systemic autoimmunity.

译文

Rai (ShcC) 属于Shc衔接蛋白家族,在神经元细胞中表达,在那里它充当激活PI3K/Akt存活途径的存活因子。在体内,Rai保护大脑免受缺血性损伤。在这项研究中,我们表明Rai在T和B淋巴细胞中表达。基于Rai(-/-) 小鼠持续发展脾肿大的发现,讨论了Rai在淋巴细胞稳态和增殖中的作用。令人惊讶的是,与神经元相反,Rai被发现会损害淋巴细胞的存活。此外,Rai缺乏导致外周T细胞的频率减少,同时b细胞的频率增加。Rai(-/-) 淋巴细胞在体外对Ag受体参与表现出增强的增殖反应,这与TCR和BCR增强的信号传导以及体内对变应原致敏的更强大反应有关。高比例的Rai(-/-) 小鼠发展为狼疮样自身免疫综合征,其特征是脾肿大,自发外周T和b细胞活化,自身抗体产生以及免疫复合物在肾小球中的沉积,从而导致自身免疫性肾小球肾炎。数据将Rai确定为淋巴细胞存活和激活的负调节剂,并表明该蛋白的丢失导致免疫耐受的破坏和全身自身免疫的发展。

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