The interleukin 7 receptor is required for T cell receptor gamma locus accessibility to the V(D)J recombinase.
The interleukin 7 receptor is required for T cell receptor gamma locus accessibility to the V(D)J recombinase.
复制标题
DOI：
10.1084/jem.191.6.1045
复制
发表时间：
2000-03-20
期刊：
影响因子：
--
通讯作者：
Muegge K
中科院分区：
文献类型：
--
作者：
Schlissel MS;Durum SD;Muegge K
白细胞介素（IL）-7信号转导通路的缺陷导致人类和小鼠严重的免疫缺陷。在IL-7受体缺陷（IL-7 R −/−）小鼠中，淋巴前体细胞的存活率降低，可变/多样性/连接区V（D）J重组在不同位点受到不同影响，在T细胞受体（TCR）-γ位点被阻滞，在免疫球蛋白重链（IgH）位点异常，在TCR-β位点延迟。在这里，我们分析TCR-γ基因座的重组缺陷。使用连接介导的聚合酶链反应，我们寻求重组过程的中间体。在不存在IL-7信号的情况下，未观察到TCR-γ基因座的重组起始，而可检测到TCR-β基因座处的重组中间体。因此，重排TCR-γ基因座的失败是由于未能启动切割而不是未能重新连接断裂的DNA末端。以前认为V（D）J重组开始于T细胞发育的pro-T2阶段，在pro-T1阶段IL-7 R −/−胸腺细胞停滞之后。然而，在这里，我们发现TCR-γ和-β重组中间体在正常T1细胞中很容易检测到，但在IL-7 R −/− T1细胞中只检测到TCR-β中间体，支持IL-7在TCR-γ基因座重排中的机制作用。由于在不存在IL-7信号的情况下报告了减少的重组激活基因（rag）表达，我们直接测试了TCR-γ基因座是否可被重组Rag蛋白体外切割。我们发现，与野生型相比，IL-7 R −/−胸腺细胞中Rag介导的切割的染色质可及性降低。因此，IL-7通过调节基因座可及性来控制TCR-γ基因座处的重组。
Defects in the interleukin (IL)-7 signal transduction pathway lead to severe immunodeficiency in humans and in mice. In IL-7 receptor–deficient (IL-7R−/−) mice, lymphoid precursors show a reduced survival rate and variable/diversity/joining region V(D)J recombination is variously affected in different loci, being arrested in the T cell receptor (TCR)-γ locus, aberrant in the immunoglobulin heavy chain (IgH) locus, and delayed in the TCR-β locus. Here, we analyze the recombination defect of the TCR-γ locus. Using ligation-mediated polymerase chain reaction, we sought intermediates of the recombination process. In the absence of the IL-7 signal, no initiation of recombination of the TCR-γ locus was observed, whereas recombination intermediates at the TCR-β locus could be detected. Thus, the failure to rearrange the TCR-γ locus is due to a failure to initiate cleavage rather than a failure to religate broken DNA ends. V(D)J recombination was previously thought to begin at the pro-T2 stage of T cell development after the arrest of IL-7R−/− thymocytes at the pro-T1 stage. However, here we show that both TCR-γ and -β recombination intermediates are readily detectable in normal T1 cells, but only TCR-β intermediates were detected in IL-7R−/− T1 cells, supporting a mechanistic role for IL-7 in TCR-γ locus rearrangement. Since reduced recombination activating gene (rag) expression has been reported in the absence of the IL-7 signal, we directly tested whether the TCR-γ locus is accessible to cleavage by recombinant Rag proteins in vitro. We found a reduction in chromatin accessibility for Rag-mediated cleavage in IL-7R−/− thymocytes compared with wild-type. Thus, IL-7 controls recombination at the TCR-γ locus by regulating locus accessibility.
登录
查看更多内容
DOI：
10.1084/jem.184.6.2423
发表时间：
1996-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Maki K;Sunaga S;Ikuta K
通讯作者：
Ikuta K
影响因子：
64.5
作者：
StanhopeBaker, P;Hudson, KM;Schlissel, MS
通讯作者：
Schlissel, MS
影响因子：
64.8
作者：
MACCHI, P;VILLA, A;NOTARANGELO, LD
通讯作者：
NOTARANGELO, LD
影响因子：
7.8
作者：
Schlissel, M S;Stanhope-Baker, P
通讯作者：
Stanhope-Baker, P
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
发表时间：
1998-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Durum SK;Candèias S;Nakajima H;Leonard WJ;Baird AM;Berg LJ;Muegge K
通讯作者：
Muegge K