Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction
Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction
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DOI：
10.1016/j.immuni.2004.07.013
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发表时间：
2004-08-01
期刊：
影响因子：
32.4
通讯作者：
Penninger, JM
中科院分区：
文献类型：
--
作者：
Jeon, MS;Atfield, A;Penninger, JM
抗原特异性免疫耐受限制了自身免疫性疾病中涉及的自身反应性T细胞的扩增。在这里，我们表明，E3泛素连接酶CbI-b在T细胞耐受信号后上调。小鼠中CbI-b的缺失导致体外和体内T细胞耐受的诱导受损。重要的是，用耐受性抗原再攻击CbI-b突变小鼠导致大规模致死。此外，CbI-b的消融导致自身免疫加重。从机制上讲，CbI-b拯救的损失减少了无反应性T细胞的钙动员，这归因于CbI-b介导的PLC γ-1磷酸化调节。我们的研究结果表明，CbI-b在调节外周耐受性和T细胞无反应性的关键作用。
Antigen-specific immunotolerance limits the expansion of self-reactive T cells involved in autoimmune diseases. Here, we show that the E3 ubiquitin ligase CbI-b is upregulated in T cells after tolerizing signals. Loss of CbI-b in mice results in impaired induction of T cell tolerance both in vitro and in vivo. Importantly, rechallenge of CbI-b mutant mice with the tolerizing antigen results in massive lethality. Moreover, ablation of CbI-b resulted in exacerbated autoimmunity. Mechanistically, loss of CbI-b rescues reduced calcium mobilization of anergic T cells, which was attributed to CbI-b-mediated regulation of PLCgamma-1 phosphorylation. Our results show a critical role for CbI-b in the regulation of peripheral tolerance and anergy of T cells.