Mondino A, Whaley C D, DeSilva D R, Li W, Jenkins M K, Mueller D L
Department of Microbiology, University of Minnesota, Minneapolis 55455, USA.
J Immunol. 1996 Sep 1;157(5):2048-57.
Anergic CD4+ Th cells do not produce IL-2 when challenged with Ag-pulsed accessory cells because of a transcriptional defect. In this work, we report that these anergic T cells are defective in their ability to up-regulate protein binding and transactivation at two critical IL-2 DNA enhancer elements: NF-AT (nuclear factor of activated T cells; a sequence that binds a heterotrimeric NFATp, Fos, and Jun protein complex) and Activator Protein-1 (AP-1) (that binds Fos and Jun heterodimers). Western blot analysis of nuclear extracts showed that the impaired DNA-protein interactions in anergic T cells were associated with poor expression of the inducible AP-1 family members c-Fos, FosB, and JunB. However, the reduced expression of these proteins was not the result of a global TCR/CD3-signaling defect because CD3 cross-linking induced an equivalent increase in intracellular-free calcium ions, as well as NFATp dephosphorylation, translocation to the nucleus, and DNA binding in both normal and anergic T cells. Thus, defective IL-2 gene transcription appears to be due, at least in part, to a selective block in the expression of the AP-1 Fos and Jun family members in anergic T cells.
无反应性CD4 + Th细胞在受到抗原脉冲刺激的辅助细胞刺激时，由于转录缺陷而不产生IL-2。在这项研究中，我们报告这些无反应性T细胞在两个关键的IL-2 DNA增强子元件上上调蛋白质结合和反式激活的能力存在缺陷：NF-AT（活化T细胞核因子；一种结合异源三聚体NFATp、Fos和Jun蛋白复合物的序列）和激活蛋白-1（AP-1）（结合Fos和Jun异二聚体）。对核提取物的蛋白质印迹分析表明，无反应性T细胞中受损的DNA-蛋白质相互作用与诱导型AP-1家族成员c-Fos、FosB和JunB的表达不佳有关。然而，这些蛋白质表达的降低并非全局TCR/CD3信号缺陷的结果，因为CD3交联在正常和无反应性T细胞中均诱导细胞内游离钙离子等效增加，以及NFATp去磷酸化、转位至细胞核和DNA结合。因此，IL-2基因转录缺陷似乎至少部分是由于无反应性T细胞中AP-1 Fos和Jun家族成员表达的选择性阻滞。
