Differential effects of zeta and eta transgenes on early alpha/beta T cell development.
Differential effects of zeta and eta transgenes on early alpha/beta T cell development.
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DOI：
10.1084/jem.179.5.1485
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发表时间：
1994-05-01
影响因子：
15.3
通讯作者：
Singer, A
中科院分区：
文献类型：
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作者：
Love, P E;Shores, E W;Lee, E J;Grinberg, A;Munitz, T I;Westphal, H;Singer, A
ζ-家族二聚体（ζ、η和γ）是一组结构和功能相关的蛋白质，其在发育中的胸腺细胞中表达，并作为T细胞抗原受体（TCR）和某些IG Fc受体的信号转导亚基起作用。ζ、η和γ各自含有一个或多个拷贝的已知为信号转导所需的保守的基于酪氨酸的活化基序（TAM）。为了检查多个或单个TAM元件的发育重要性，我们产生了在人CD 2启动子和调节元件的控制下表达以下的转基因小鼠：（a）全长（FL）ζ链（3个TAM）;（B）η链，衍生自选择性剪接的天然存在的ζ变体（2个TAM）;或（c）截短的ζ链（CT 108; 1个TAM）。出乎意料的是，我们发现FL zeta链的过表达导致RAG-1和RAG-2表达的过早终止，阻止了TCR-α和TCR-β基因的生产性重排，并阻断了胸腺细胞进入CD 4/CD 8发育途径。相反，我们发现eta或CT 108的过度表达对正常胸腺细胞成熟没有影响。这些结果表明，在前体TCR-胸腺细胞中存在早期信号传导途径，其可以调节RAG-1和RAG-2表达，并且对ζ-家族二聚体的个体成员有差异应答。
The zeta-family dimers (zeta, eta, and gamma) are a group of structurally and functionally related proteins that are expressed in developing thymocytes and function as signal transducing subunits of the T cell antigen receptor (TCR) and certain Ig Fc receptors. Zeta, eta, and gamma each contain one or more copies of a conserved tyrosine- based activation motif (TAM) that is known to be required for signal transduction. To examine the developmental importance of multiple or individual TAM elements we generated transgenic mice that express: (a) full-length (FL) zeta-chain (3 TAMs); (b) eta-chain, a naturally occurring variant of zeta that is derived from alternative splicing (2 TAMs); or (c) truncated zeta-chain (CT108; 1 TAM), under the control of the human CD2 promoter and regulatory elements. Unexpectedly, we found that overexpression of the FL zeta chain caused premature termination of RAG-1 and RAG-2 expression, prevented productive rearrangement of the TCR-alpha and TCR-beta genes and blocked entry of thymocytes into the CD4/CD8 developmental pathway. In contrast, we found that overexpression of eta or CT108 had no effect on normal thymocyte maturation. These results suggest that an early signaling pathway exists in precursor TCR- thymocytes that can regulate RAG-1 and RAG-2 expression and is differentially responsive to individual members of the zeta-family dimers.