Interleukin 7 receptor control of T cell receptor gamma gene rearrangement: role of receptor-associated chains and locus accessibility.
Interleukin 7 receptor control of T cell receptor gamma gene rearrangement: role of receptor-associated chains and locus accessibility.
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白介素7受体伽马基因重排的受体控制：受体相关链和位点可及性的作用。
DOI：
10.1084/jem.188.12.2233
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发表时间：
1998-12-21
期刊：
影响因子：
--
通讯作者：
Muegge K
中科院分区：
文献类型：
--
作者：
Durum SK;Candèias S;Nakajima H;Leonard WJ;Baird AM;Berg LJ;Muegge K
T细胞受体和免疫球蛋白基因座的VDJ重组发生在未成熟的淋巴细胞中。虽然DNA切割和连接的分子机制已经变得更加清楚，但还不清楚是什么控制了哪些靶位点发生重排。在白细胞介素7受体（IL-7 R）α−/−小鼠胸腺细胞中，T细胞受体（TCR）-γ位点的重排几乎被废除，而其他重排位点受到的影响不太严重。通过检查具有靶向突变的不同品系小鼠，我们现在观察到从IL-7 R α到TCR-γ位点重排的信号传导通路需要γc受体链和γ c相关Janus激酶Jak 3。在IL-7 R α−/−胸腺细胞中，TCR-γ基因座产生无菌转录本的过程（通常先于基因座重排）受到极大抑制。抑制的转录不是由于缺乏转录因子，因为已知调节该位点的三种转录因子在IL-7 R α−/−胸腺细胞中很容易检测到。相反，TCR-γ基因座在IL-7 R α−/−胸腺细胞中被甲基化。用特异性组蛋白去乙酰化酶抑制剂利司他汀A处理IL-7 R α−/−前体T细胞，可以解除TCR-γ基因重排的阻断。该数据支持IL-7 R通过基因座的去甲基化和组蛋白乙酰化调节基因座的可及性来促进TCR-γ基因重排的模型。
VDJ recombination of T cell receptor and immunoglobulin loci occurs in immature lymphoid cells. Although the molecular mechanisms of DNA cleavage and ligation have become more clear, it is not understood what controls which target loci undergo rearrangement. In interleukin 7 receptor (IL-7R)α−/− murine thymocytes, it has been shown that rearrangement of the T cell receptor (TCR)-γ locus is virtually abrogated, whereas other rearranging loci are less severely affected. By examining different strains of mice with targeted mutations, we now observe that the signaling pathway leading from IL-7Rα to rearrangement of the TCR-γ locus requires the γc receptor chain and the γc-associated Janus kinase Jak3. Production of sterile transcripts from the TCR-γ locus, a process that generally precedes rearrangement of a locus, was greatly repressed in IL-7Rα−/− thymocytes. The repressed transcription was not due to a lack in transcription factors since the three transcription factors known to regulate this locus were readily detected in IL-7Rα−/− thymocytes. Instead, the TCR-γ locus was shown to be methylated in IL-7Rα−/− thymocytes. Treatment of IL-7Rα−/− precursor T cells with the specific histone deacetylase inhibitor trichostatin A released the block of TCR-γ gene rearrangement. This data supports the model that IL-7R promotes TCR-γ gene rearrangement by regulating accessibility of the locus via demethylation and histone acetylation of the locus.