Zhan Yifan, Gerondakis Steve, Coghill Elise, Bourges Dorothee, Xu Yuekang, Brady Jamie L, Lew Andrew M
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
J Immunol. 2008 Oct 15;181(8):5405-13. doi: 10.4049/jimmunol.181.8.5405.
Although the transcription factor Foxp3 is implicated in regulating glucocorticoid-induced TNF receptor (GITR) expression in the T regulatory cell lineage, little is known about how GITR is transcriptionally regulated in conventional T cells. In this study, we provide evidence that TCR-mediated GITR expression depends on the ligand affinity and the maturity of conventional T cells. A genetic dissection of GITR transcriptional control revealed that of the three transcription factors downstream of the classical NF-kappaB pathway (RelA, cRel, and NF-kappaB1), RelA is a critical positive regulator of GITR expression, although cRel and NF-kappaB1 also play a positive regulatory role. Consistent with this finding, inhibiting NF-kappaB using Bay11-7082 reduces GITR up-regulation. In contrast, NFAT acts as a negative regulator of GITR expression. This was evidenced by our findings that agents suppressing NFAT activity (e.g., cyclosporin A and FK506) enhanced TCR-mediated GITR expression, whereas agents enhancing NFAT activity (e.g., lithium chloride) suppressed TCR-mediated GITR up-regulation. Critically, the induction of GITR was found to confer protection to conventional T cells from TCR-mediated apoptosis. We propose therefore that two major transcriptional factors activated downstream of the TCR, namely, NF-kappaB and NFAT, act reciprocally to balance TCR-mediated GITR expression in conventional T cells, an outcome that appears to influence cell survival.
尽管转录因子Foxp3参与调节调节性T细胞谱系中糖皮质激素诱导的TNF受体（GITR）的表达，但对于常规T细胞中GITR的转录调控方式却知之甚少。在本研究中，我们提供证据表明，TCR介导的GITR表达取决于常规T细胞的配体亲和力和成熟度。对GITR转录控制的遗传学剖析表明，在经典NF-κB途径下游的三种转录因子（RelA、cRel和NF-κB1）中，RelA是GITR表达的关键正调控因子，尽管cRel和NF-κB1也发挥正调控作用。与这一发现一致，使用Bay11-7082抑制NF-κB可降低GITR的上调。相反，NFAT作为GITR表达的负调控因子。我们的研究结果证明了这一点，即抑制NFAT活性的试剂（如环孢素A和FK506）增强了TCR介导的GITR表达，而增强NFAT活性的试剂（如氯化锂）则抑制了TCR介导的GITR上调。至关重要的是，发现GITR的诱导赋予常规T细胞对TCR介导的凋亡的保护作用。因此，我们提出，TCR下游激活的两个主要转录因子，即NF-κB和NFAT，相互作用以平衡常规T细胞中TCR介导的GITR表达，这一结果似乎影响细胞存活。
