The interleukin 7 receptor is required for T cell receptor γ locus accessibility to the V(D)J recombinase

被引:85
作者
Schlissel, MS
Durum, SD
Muegge, K
机构
[1] NCI, Intramural Res Support Program, Sci Applicat Int Corp, SAIC Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA
[2] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA
[3] NCI, Mol Immunoregulat Lab, Sci Applicat Int Corp, SAIC Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA
关键词
recombination; T lymphocytes; interleukins; chromatin; immunology;
D O I
10.1084/jem.191.6.1045
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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)-gamma locus, aberrant in the immunoglobulin heavy chain (IgH) locus, and delayed in the TCR)-gamma locus. Here, we analyze the recombination defect of the TCR-gamma 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-gamma locus was observed, whereas recombination intermediates at the TCR-beta locus could be detected. Thus, the failure to rearrange the TCR-gamma 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-gamma and -beta recombination intermediates are readily detectable in normal T1 cells, but only TCR-beta intermediates were detected in IL-7R(-/-) T1 cells, supporting a mechanistic role for IL-7 in TCR-gamma 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-gamma 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-gamma locus by regulating locus accessibility.
引用
收藏
页码:1045 / 1050
页数:6
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