NF-κB is crucial in proximal T-cell signaling for calcium influx and NFAT activation.
NF-κB is crucial in proximal T-cell signaling for calcium influx and NFAT activation.
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DOI：
10.1002/eji.201444904
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发表时间：
2014-12
影响因子：
5.4
通讯作者：
Beg, Amer A.
中科院分区：
文献类型：
--
作者：
Bronk, Crystina C.;Yoder, Sean;Hopewell, Emily L.;Yang, Shengyu;Celis, Esteban;Yu, Xue-Zhong;Beg, Amer A.
在公认的T细胞激活模型中，平行的信号转导通路激活转录因子NF-κB、NFAT和AP-1，以驱动T细胞对抗原的克隆性增殖。在C57BL/6小鼠T细胞中，抗原诱导的CD8+T细胞激活后的全基因组转录图谱显示，在缺乏NF-κB p50和cRel亚基的情况下，受NFAT调控的基因也减少了。重要的是，与WT或−/−−/−CD8+T细胞相比，p50θ−/−cRel CD8+T细胞显著降低了NFAT和AP-1的活性。与钙内流减少、PLCγ和ZAP70激活有关。有趣的是，药物旁路的γ调节通路在很大程度上挽救了p50−/−cRel−/−T细胞增殖性缺陷。这些结果表明，在近端κ信号和钙反应中，对NF-TCRB p50和cRel亚基的需求是至关重要的和意想不到的。他们进一步提出，在缺乏NF-κB途径组件的情况下，T细胞中的关键缺陷可能是由于近端T细胞信号受损所致。
In the accepted model of T-cell activation, parallel signal transduction pathways activate the transcription factors NF-κB, NFAT and AP-1 to drive clonal expansion of T cells in response to antigen. Genome-wide transcriptional profiling following antigen-induced CD8+ T-cell activation in C57BL/6 mouse T cells revealed that genes regulated by NFAT were also reduced in the absence of NF-κB p50 and cRel subunits. Importantly, p50−/−cRel−/− CD8+ T cells had significantly diminished NFAT and AP-1 activation compared with WT or PKCθ−/− CD8+ T cells. Attenuated NFAT activation after TCR engagement was associated with reduced calcium influx, PLCγ and Zap70 activation. Interestingly, pharmacological bypass of PLCγ regulated pathways largely rescued p50−/−cRel−/− T-cell proliferative defects. These results indicate a crucial and unexpected requirement for NF-κB p50 and cRel subunits in proximal TCR signaling and calcium responses. They further suggest that key defects in T cells in the absence of NF-κB pathway components may be due to impaired proximal T-cell signaling.
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