The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms1
The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms1
复制标题
胸腺基质中表达的 Gli3 转录因子通过 Hedgehog 依赖性和独立机制控制胸腺细胞负选择1
作者：
A. L. Hager;A. Furmanski;S. Ross;S. Outram;N. Rowbotham;T. Crompton
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，我们表明，Gli3，未检测到成人胸腺细胞，在小鼠胎儿和成人胸腺基质中表达。PCR阵列分析显示Cxcl9、Rbp1和Nos2是Gli3的新靶基因。我们发现，Gli3积极调节这些基因的表达，最有可能通过抑制中间阻遏物。自身反应性胸腺细胞的缺失依赖于它们与胸腺基质的相互作用。Gli3突变体中促凋亡基因Nos2的抑制与在体外和体内进行阴性选择的双阳性胸腺细胞的凋亡减少以及自身反应性胸腺细胞的产生相一致。综上所述，这些数据表明，Gli3控制胸腺细胞凋亡和负选择可能通过调节Nos2。胸腺基质中Gli3表达缺陷也导致成熟胸腺细胞上CD5表达降低和MHC I类选择性CD4+细胞的不适当产生，两者均与TCR信号强度降低一致。总的来说，我们的数据表明，Gli3表达在胸腺基质调节负选择和TCR信号强度通过Hh依赖和非依赖机制，与自身免疫的影响。
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.
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DOI：
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发表时间：
2007
期刊：
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影响因子：
--
作者：
K. Laky;B. Fowlkes
通讯作者：
K. Laky;B. Fowlkes
影响因子：
32.4
作者：
Sharp, LL;Schwarz, DA;Hedrick, SM
通讯作者：
Hedrick, SM
影响因子：
4.6
作者：
M. Matise;D. Epstein;Heidi L. Park;K. Platt;A. Joyner
通讯作者：
M. Matise;D. Epstein;Heidi L. Park;K. Platt;A. Joyner
影响因子：
9.8
作者：
Johnston, JJ;Olivos-Glander, I;Biesecker, LG
通讯作者：
Biesecker, LG
影响因子：
32.4
作者：
Anderson, MS;Venanzi, ES;Mathis, D
通讯作者：
Mathis, D