The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms
The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms
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DOI：
10.4049/jimmunol.0900152
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发表时间：
2009-09-01
影响因子：
4.4
通讯作者：
Crompton, Tessa
中科院分区：
文献类型：
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作者：
Hager-Theodorides, Ariadne L.;Furmanski, Anna L.;Crompton, Tessa
Hedgehog (Hh) 反应性转录因子 Gli3 是胎儿胸腺细胞有效发育所必需的。在这项研究中，我们发现 Gli3 在小鼠胎儿和成人胸腺基质中表达，但在成人胸腺细胞中未检测到。 PCR阵列分析显示Cxcl9、Rbp1和Nos2是Gli3的新靶基因。我们发现 Gli3 很可能通过抑制中间阻遏物来正向调节这些基因的表达。自身反应性胸腺细胞的删除取决于它们与胸腺基质的相互作用。 Gli3突变体中促凋亡基因Nos2的抑制与体外和体内负选择中双阳性胸腺细胞凋亡的减少以及自身反应性胸腺细胞的产生同时发生。综上所述，这些数据表明 Gli3 可能通过 Nos2 的调节来控制胸腺细胞凋亡和负选择。胸腺基质中的缺陷Gli3表达还导致成熟胸腺细胞上CD5表达降低以及MHC I类选择的CD4(+)细胞的不适当产生，两者均与TCR信号强度降低一致。总体而言，我们的数据表明，胸腺基质中表达的 Gli3 通过 Hh 依赖性和独立机制调节负选择和 TCR 信号强度，对自身免疫产生影响。免疫学杂志，2009，183：3023-3032。
The Hedgehog (Hh) responsive transcription factor Gli3 is required for efficient thymocyte development in the fetus. In this study we show that Gli3, not detected in adult thymocytes, is expressed in the murine fetal and adult thymus stroma. PCR array analysis revealed Cxcl9, Rbp1, and Nos2 as novel target genes of Gli3. We show that Gli3 positively regulates the expression of these genes, most likely by suppressing an intermediate repressor. Deletion of autoreactive thymocytes depends on their interactions with the thymus stroma. Repression of the proapoptotic gene Nos2 in Gli3 mutants coincides with reduced apoptosis of double positive thymocytes undergoing negative selection in vitro and in vivo, and the production of autoreactive thymocytes. Taken together these data indicate that Gli3 controls thymocyte apoptosis and negative selection possibly via the regulation of Nos2. Defective Gli3 expression in the thymus stroma also resulted in decreased CD5 expression on mature thymocytes and inappropriate production of MHC class I-selected CD4(+) cells, both consistent with reduced TCR signal strength. Overall our data indicate that Gli3 expressed in the thymus stroma regulates negative selection and TCR signal strength via Hh-dependent and -independent mechanisms, with implications for autoimmunity. The Journal of Immunology, 2009, 183: 3023-3032.