NFAT5 induction by the pre-T-cell receptor serves as a selective survival signal in T-lymphocyte development
NFAT5 induction by the pre-T-cell receptor serves as a selective survival signal in T-lymphocyte development
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DOI：
10.1073/pnas.1215934110
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发表时间：
2013-10-01
影响因子：
11.1
通讯作者：
Lopez-Rodriguez, Cristina
中科院分区：
文献类型：
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作者：
Berga-Bolanos, Rosa;Alberdi, Maria;Lopez-Rodriguez, Cristina
Rel样转录因子核因子-kappaB(NF-kappa B)和钙调神经磷酸酶依赖的活化T细胞核因子(NFATc)控制胸腺细胞成熟的特定点。胸腺细胞也表达REL家族中的一个独特的成员，不依赖钙调神经磷酸酶的渗透压反应调节因子NFAT5。在这里，我们发现IKKβ调节胸腺细胞中NFAT5的表达，进而促进T细胞受体αβ胸腺细胞的存活，并以渗透压非依赖的方式从β选择检查点过渡到双阳性阶段。NFAT5基因缺陷的胸腺细胞具有正常的前T细胞受体表达和近端信号，但表现出部分β链等位基因排除缺陷和细胞凋亡增加。进一步分析表明，NFAT5可调节细胞生存因子A1和Bcl2的表达，并抑制促凋亡的P53/Noxa轴。这些发现将NFAT5定位为胸腺细胞中IKKβ/NF-kappa B途径的靶点，并作为T细胞前受体生存作用的下游效应器。
The Rel-like transcription factors nuclear factor kappa B (NF-kappa B) and the calcineurin-dependent nuclear factor of activated T cells (NFATc) control specific points of thymocyte maturation. Thymocytes also express a distinct member of the Rel family, the calcineurin-independent, osmostress response regulator NFAT5. Here we show that IKK beta regulates the expression of NFAT5 in thymocytes, which in turn contributes to the survival of T-cell receptor alpha beta thymocytes and the transition from the beta-selection checkpoint to the double-positive stage in an osmostress-independent manner. NFAT5-deficient thymocytes had normal expression and proximal signaling of the pre-T-cell receptor but exhibited a partial defect in beta-chain allelic exclusion and increased apoptosis. Further analysis showed that NFAT5 regulated the expression of the prosurvival factors A1 and Bcl2 and attenuated the proapoptotic p53/Noxa axis. These findings position NFAT5 as a target of the IKK beta/NF-kappa B pathway in thymocytes and as a downstream effector of the prosurvival role of the pre-T-cell receptor.