Dampening of death pathways by schnurri-2 is essential for T-cell development.
Dampening of death pathways by schnurri-2 is essential for T-cell development.
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DOI：
10.1038/nature09848
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发表时间：
2011-04-07
期刊：
影响因子：
64.8
通讯作者：
Glimcher, Laurie H.
中科院分区：
文献类型：
--
作者：
Staton, Tracy L.;Lazarevic, Vanja;Jones, Dallas C.;Lanser, Amanda J.;Takagi, Tsuyoshi;Ishii, Shunsuke;Glimcher, Laurie H.
产生多样性和自身耐受性T细胞库需要通过CD 4 + CD 8+双阳性（DP）胸腺细胞对T细胞受体（TCR）信号进行适当的解释。胸腺细胞命运由TCR：MHC-肽相互作用的性质决定，其中较高强度的信号导致死亡（阴性选择），中等强度的信号导致分化（阳性选择）。已经描述了通过调节TCR信号强度来调节T细胞发育的分子，但是具体限定阳性选择和阴性选择之间的边界的组分仍然未知。在这里，我们表明，抑制TCR诱导的死亡途径是至关重要的正确解释积极的选择信号在体内，并确定Schnurri 2（Shn 2）作为一个关键的死亡损伤。我们的研究结果表明，Shn 2 −/− DP胸腺细胞不适当地进行负选择，以响应积极的选择信号，从而导致破坏T细胞发育。Shn 2 −/− DP胸腺细胞在体外对TCR诱导的死亡更敏感，在体内对正选择相互作用的反应中死亡。然而，当TCR诱导的死亡被基因消融时，Shn 2缺陷型胸腺细胞可以被阳性选择。Shn 2水平在TCR刺激后增加，表明多个TCR：MHC-肽相互作用的整合可以微调死亡阈值。从机制上讲，Shn 2在TCR近端信号传导组分的下游起作用，以抑制Bax活化和线粒体死亡途径。我们的发现揭示了T细胞发育的关键调节因子，它控制着死亡和分化之间的平衡。
Generation of a diverse and self-tolerant T cell repertoire requires appropriate interpretation of T cell receptor (TCR) signals by CD4+CD8+ double positive (DP) thymocytes. Thymocyte cell fate is dictated by the nature of TCR:MHC-peptide interactions, with signals of higher strength leading to death (negative selection) and signals of intermediate strength leading to differentiation (positive selection). Molecules that regulate T cell development by modulating TCR signal strength have been described but components that specifically define the boundaries between positive and negative selection remain unknown. Here we show that repression of TCR-induced death pathways is critical for proper interpretation of positive selecting signals in vivo, and identify Schnurri2 (Shn2) as a crucial death dampener. Our results indicate that Shn2−/− DP thymocytes inappropriately undergo negative selection in response to positive selecting signals, thus leading to disrupted T cell development. Shn2−/− DP thymocytes are more sensitive to TCR-induced death in vitro and die in response to positive selection interactions in vivo. However, Shn2-deficient thymocytes can be positively selected when TCR-induced death is genetically-ablated. Shn2 levels increase after TCR stimulation suggesting that integration of multiple TCR:MHC-peptide interactions may fine tune the death threshold. Mechanistically, Shn2 functions downstream of TCR proximal signaling compenents to dampen Bax activation and the mitochondrial death pathway. Our findings uncover a critical regulator of T cell development that controls the balance between death and differentiation.
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