NF-κB Protects NKT Cells from Tumor Necrosis Factor Receptor 1-induced Death.
NF-κB Protects NKT Cells from Tumor Necrosis Factor Receptor 1-induced Death.
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DOI：
10.1038/s41598-017-15461-y
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发表时间：
2017-11-15
影响因子：
4.6
通讯作者：
Joyce S
中科院分区：
文献类型：
--
作者：
Kumar A;Gordy LE;Bezbradica JS;Stanic AK;Hill TM;Boothby MR;Van Kaer L;Joyce S
半不变自然杀伤T （NKT）细胞是具有免疫调节特性的先天性淋巴细胞。NKT细胞在发育过程中存活需要激活RelA/NF-κB进行信号处理。尽管如此，在发育中的NKT细胞中，NF-κB整合的上游信号仍不完全明确。我们发现，将编码bcl - xl的Bcl2l1基因导入NF-κB信号缺陷IκBΔN转基因小鼠中，可以挽救NKT细胞的发育和分化。我们推断，NF-κB活化保护发育中的NKT细胞免受T细胞受体（TCR）或死亡受体（如肿瘤坏死因子受体1 （TNFR1）或Fas）高亲和力激动剂识别发出的死亡信号的影响。令人惊讶的是，PKC-θ或carma -1 （NKT TCR近端信号节点的两个信号传感器）的单一和联合缺陷仅部分重现了IκBΔN tg小鼠中观察到的NKT细胞缺陷。因此，将Bcl2l1基因导入PKC-θ缺失的小鼠，并不能挽救NKT细胞的发育。相反，在IκBΔN tg小鼠中，tnfr1缺失而非fas缺失挽救了NKT细胞的发育。与这一发现一致的是，在体外实验中，用抑制下游NF-κB活化的κB激酶抑制剂的拮抗剂处理胸腺细胞可使NKT细胞对TNF-α-诱导的细胞死亡增敏。因此，我们得出结论，NF-κB的信号整合保护发育中的NKT细胞免受来自TNFR1的死亡信号的影响，而不是来自NKT TCR或Fas的死亡信号。
Semi-invariant natural killer T (NKT) cells are innate-like lymphocytes with immunoregulatory properties. NKT cell survival during development requires signal processing by activated RelA/NF-κB. Nonetheless, the upstream signal(s) integrated by NF-κB in developing NKT cells remains incompletely defined. We show that the introgression of Bcl-xL-coding Bcl2l1 transgene into NF-κB signalling-deficient IκBΔN transgenic mouse rescues NKT cell development and differentiation in this mouse model. We reasoned that NF-κB activation was protecting developing NKT cells from death signals emanating either from high affinity agonist recognition by the T cell receptor (TCR) or from a death receptor, such as tumor necrosis factor receptor 1 (TNFR1) or Fas. Surprisingly, the single and combined deficiency in PKC-θ or CARMA-1—the two signal transducers at the NKT TCR proximal signalling node—only partially recapitulated the NKT cell deficiency observed in IκBΔN tg mouse. Accordingly, introgression of the Bcl2l1 transgene into PKC-θ null mouse failed to rescue NKT cell development. Instead, TNFR1-deficiency, but not the Fas-deficiency, rescued NKT cell development in IκBΔN tg mice. Consistent with this finding, treatment of thymocytes with an antagonist of the inhibitor of κB kinase —which blocks downstream NF-κB activation— sensitized NKT cells to TNF-α-induced cell death in vitro. Hence, we conclude that signal integration by NF-κB protects developing NKT cells from death signals emanating from TNFR1, but not from the NKT TCR or Fas.
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影响因子：
30.5
作者：
通讯作者：
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DOI：
10.4049/jimmunol.1003965
发表时间：
2011-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gordy LE;Bezbradica JS;Flyak AI;Spencer CT;Dunkle A;Sun J;Stanic AK;Boothby MR;He YW;Zhao Z;Van Kaer L;Joyce S
通讯作者：
Joyce S
影响因子：
20.3
作者：
Crawford, Greg;Enders, Anselm;Cornall, Richard J.
通讯作者：
Cornall, Richard J.
影响因子：
11.4
作者：
Cheng, LEC;Chan, FKM;Winoto, A
通讯作者：
Winoto, A
影响因子：
32.4
作者：
Kain, Lisa;Webb, Bill;Anderson, Brian L.;Deng, Shenglou;Holt, Marie;Costanzo, Anne;Zhao, Meng;Self, Kevin;Teyton, Anais;Everett, Chris;Kronenberg, Mitchell;Zajonc, Dirk M.;Bendelac, Albert;Savage, Paul B.;Teyton, Luc
通讯作者：
Teyton, Luc