Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion
Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion
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DOI：
10.1073/pnas.1200090109
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发表时间：
2012-03-06
影响因子：
11.1
通讯作者：
Benoist, Christophe
中科院分区：
文献类型：
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作者：
Fassett, Marlys S.;Jiang, Wenyu;Benoist, Christophe
表达自身反应性T细胞受体（TCR）的未成熟胸腺细胞可以采用不同的细胞命运：通过细胞凋亡或偏离到替代谱系如FoxP 3（+）调节性T细胞（Treg）的克隆缺失。我们重新审视了转录因子Nr 4a 1（Nur 77）的作用，这是一种由TCR参与诱导的立即早期反应基因。Nr 4a 1 KO小鼠在抗原诱导的克隆缺失中显示出明显的定量缺陷。Nr 4a 1缺失的影响并不因促凋亡因子Bim的缺失而增强。此外，在TCR转基因小鼠和非转基因小鼠中，Nr 4a 1缩短了向Treg谱系的初始分化。在选择条件下Nr 4a 1 KO胸腺细胞的转录谱显示Nr 4a 1激活几个靶点的转录，与这些不同的作用一致：（i）Nr 4a 1参与TCR触发后Bim的诱导;（ii）可能矛盾的是，Nr 4a 1正控制Treg标签的几个转录物，特别是Ikzf 2和Tnfrsf 9;（iii）与其在肝脏中的促存活和代谢作用一致，Nr 4a 1也是TCR诱导糖酵解和Krebs循环途径的一组协调酶所必需的，我们提出这可能与mTOR/Akt的激活一样拮抗Treg选择。因此，Nr 4a 1似乎在T细胞分化的关键时刻充当命运决定的平衡分子。
Immature thymocytes expressing autoreactive T-cell receptors (TCR) can adopt differing cell fates: clonal deletion by apoptosis or deviation into alternative lineages such as FoxP3(+) regulatory T cells (Treg). We revisited the role of the transcription factor Nr4a1 (Nur77), an immediate-early response gene induced by TCR engagement. Nr4a1KO mice show clear quantitative defects in antigen-induced clonal deletion. The impact of the Nr4a1 deletion is not enhanced by deletion of the proapoptotic factor Bim. In addition, Nr4a1 curtails initial differentiation into the Treg lineage in TCR transgenic mice and in nontransgenic mice. Transcriptional profiling of Nr4a1KO thymocytes under selection conditions reveals that Nr4a1 activates the transcription of several targets, consistent with these diverse actions: (i) Nr4a1 partakes in the induction of Bim after TCR triggering; (ii) perhaps paradoxically, Nr4a1 positively controls several transcripts of the Treg signature, in particular Ikzf2 and Tnfrsf9; (iii) consistent with its prosurvival and metabolic role in the liver, Nr4a1 is also required for the induction by TCR of a coordinated set of enzymes of the glycolytic and Krebs cycle pathways, which we propose may antagonize Treg selection as does activation of mTOR/Akt. Thus, Nr4a1 appears to act as a balancing molecule in fate determination at a critical juncture of T-cell differentiation.