Ikaros promotes rearrangement of TCR genes in an Ikaros null thymoma cell line
Ikaros promotes rearrangement of TCR genes in an Ikaros null thymoma cell line
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DOI：
10.1002/eji.201242757
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发表时间：
2013-02-01
影响因子：
5.4
通讯作者：
Kappler, John W.
中科院分区：
文献类型：
--
作者：
Collins, Bernard;Clambey, Eric T.;Kappler, John W.
Ikaros在淋巴系统的发育和维持中很重要，部分通过与染色质重塑复合物相关发挥作用。我们利用Ikaros基因缺失的小鼠胸腺瘤细胞系（JE 131）研究了Ikaros基因在前T细胞向CD 4 + CD 8+胸腺细胞转化中的作用。我们证明该细胞系携带单一功能性TCR基因重排并表达表面前TCR。JE 131细胞还在其TCR基因座的两个等位基因上携带非功能性重排。逆转录病毒重新引入Ikaros显著增加了基因座中的转录速率和TCR V/J重组，导致许多新的TCR+细胞的出现。该过程是RAG依赖性的，需要开关/蔗糖不可发酵的染色质重塑复合物，并且与Ikaros与TCR增强子的结合一致。此外，M12/核小体重塑和脱乙酰酶复合物的敲低增加了TCR重排的频率。我们的数据表明，Ikaros通过控制TCR基因座的转录和重组机制来控制T细胞中的V/J重组。JE 131细胞系应该被证明是一个非常有用的工具，用于研究这个和其他过程中涉及的前T细胞的TCR+ CD 4 + CD 8+胸腺细胞的转换的分子细节。
Ikaros is important in the development and maintenance of the lymphoid system, functioning in part by associating with chromatin-remodeling complexes. We have studied the functions of Ikaros in the transition from pre-T cell to the CD4+CD8+ thymocyte using an Ikaros null CD4CD8 mouse thymoma cell line (JE131). We demonstrate that this cell line carries a single functional TCR gene rearrangement and expresses a surface pre-TCR. JE131 cells also carry nonfunctional rearrangements on both alleles of their TCR loci. Retroviral reintroduction of Ikaros dramatically increased the rate of transcription in the locus and TCR V/J recombination resulting in the appearance of many new TCR+ cells. The process is RAG dependent, requires switch/sucrose nonfermentable chromatin-remodeling complexes and is coincident with the binding of Ikaros to the TCR enhancer. Furthermore, knockdown of Mi2/nucleosome remodeling and deacetylase complexes increased the frequency of TCR rearrangement. Our data suggest that Ikaros controls V/J recombination in T cells by controlling access of the transcription and recombination machinery to the TCR loci. The JE131 cell line should prove to be a very useful tool for studying the molecular details of this and other processes involved in the pre-T cell to TCR+ CD4+CD8+ thymocyte transition.