Early TCR expression and aberrant T cell development in mice with endogenous prerearranged T cell receptor genes
Early TCR expression and aberrant T cell development in mice with endogenous prerearranged T cell receptor genes
复制标题
DOI：
10.4049/jimmunol.179.2.928
复制
发表时间：
2007-07-15
影响因子：
4.4
通讯作者：
Weissman, Irving L.
中科院分区：
文献类型：
--
作者：
Serwold, Thomas;Hochedlinger, Konrad;Weissman, Irving L.
调节胸腺产生T细胞速率的因素仍然没有完全确定。为了测试功能性T细胞受体的产生是否限制了胸腺T细胞输出的速率，我们使用了具有内源性预先重排的TCR基因的小鼠品系LN 3 α β。在造血发育的早期，预先重排的TCR基因异常表达，表明RAG介导的重组，而不是转录因子的表达，是启动强大的TCR转录的关键决定因素。野生型（wt）和LN3 α β小鼠之间的胸腺T细胞输出率相似，表明这些小鼠中的T细胞成熟率由TCR基因重排以外的因素决定。然而，在竞争性骨髓嵌合体中，LN3 α β胸腺细胞被wt细胞竞争出局，并且未能发育超过双阴性4阶段。此外，胸腺内移植到LN 3 α β小鼠中的wt祖细胞过度增殖，表明LN 3 α β胸腺中增加的增殖信号补偿了由早期TCR表达驱动的错误T细胞发育。
The factors that regulate the rate of production of T cells by the thymus remain incompletely defined. To test whether generation of functional T cell receptors limits the rate of thymic T cell export, we made use of a line of mice, LN3 alpha beta, that have endogenously prerearranged TCR genes. The prerearranged TCR genes were expressed abnormally early in hemopoietic development, indicating that RAG-mediated recombination, rather than transcription factor expression, is the key determinant of the initiation of robust TCR transcription. Thymic T cell export rates were similar between wild-type (wt) and LN3 alpha beta mice, indicating that T cell maturation rates in these mice are determined by factors other than TCR gene rearrangement. In competitive bone marrow chimeras, however, LN3 alpha beta thymocytes were out-competed by wt cells and failed to develop beyond the double-negative 4 stage. Furthermore, wt progenitors transplanted intrathymically into LN3 alpha beta mice proliferated excessively, suggesting that increased proliferative signals in the LN3 alpha beta thymus compensate for faulty T cell development driven by early TCR expression.