Differential calcium signaling and Kv1.3 trafficking to the immunological synapse in systemic lupus erythematosus.
Differential calcium signaling and Kv1.3 trafficking to the immunological synapse in systemic lupus erythematosus.
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差异钙信号传导和KV1.3全身性红斑狼疮的免疫突触的运输。
DOI：
10.1016/j.ceca.2009.11.001
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发表时间：
2010-01
期刊：
影响因子：
4
通讯作者：
Conforti, Laura
中科院分区：
文献类型：
--
作者：
Nicolaou, Stella A.;Neumeier, Lisa;Takimoto, Koichi;Lee, Susan Molleran;Duncan, Heather J.;Kant, Shashi K.;Mongey, Anne Barbara;Filipovich, Alexandra H.;Conforti, Laura
系统性红斑狼疮(SLE)T细胞表现出多种激活信号异常，包括钙离子反应缺陷和核因子-AT核转位增加。钙信号的持续时间在特定转录因子的激活中是至关重要的，持续的钙反应激活了核因子-AT。然而，SLE T细胞内钙离子反应的分布尚不清楚。此外，导致钙离子变化的机制还不完全清楚。Kv1.3通道控制T细胞内钙离子的动态平衡。我们报道了Kv1.3转运到SLE T细胞的免疫突触(IS)的缺陷，这可能是导致钙缺陷的原因。本研究比较了SLE、正常人和类风湿关节炎(RA)供者在IS形成时单个T细胞的定量钙离子反应。此外，我们通过双光子显微镜将细胞内钙离子浓度和Kv1.3在IS中的运输联系起来。我们发现持续的[Ca~(2+)]i升高构成了对SLE T细胞抗原刺激的主要反应。这种缺陷对SLE是选择性的，因为它在RA T细胞中没有观察到。此外，我们观察到，在正常T细胞中，钙内流的终止伴随着IS中Kv1.3的永久存在，而Kv1.3过早退出IS与SLE T细胞中持续的钙反应相关。因此，我们认为Kv1.3转运异常是导致SLE T细胞内钙信号分布改变的原因之一。总体而言，这些缺陷可能部分解释了SLE患者记录的T细胞过度活跃和功能障碍。
Systemic lupus erythematosus (SLE) T cells exhibit several activation signaling anomalies including defective Ca2+ response and increased NF-AT nuclear translocation. The duration of the Ca2+ signal is critical in the activation of specific transcription factors and a sustained Ca2+ response activates NF-AT. Yet, the distribution of Ca2+ responses in SLE T cells is not known. Furthermore, the mechanisms responsible for Ca2+ alterations are not fully understood. Kv1.3 channels control Ca2+ homeostasis in T cells. We reported a defect in Kv1.3 trafficking to the immunological synapse (IS) of SLE T cells that might contribute to the Ca2+ defect. The present study compares single T cell quantitative Ca2+ responses upon formation of the IS in SLE, normal and rheumatoid arthritis (RA) donors. Also, we correlated cytosolic Ca2+ concentrations and Kv1.3 trafficking in the IS by two-photon microscopy. We found that sustained [Ca2+]i elevations constitute the predominant response to antigen stimulation of SLE T cells. This defect is selective to SLE as it was not observed in RA T cells. Further, we observed that in normal T cells termination of Ca2+ influx is accompanied by Kv1.3 permanence in the IS, while Kv1.3 premature exit from the IS correlates with sustained Ca2+ responses in SLE T cells. Thus, we propose that Kv1.3 trafficking abnormalities contribute to the altered distribution in Ca2+ signaling in SLE T cells. Overall these defects may explain in part the T cell hyperactivity and dysfunction documented in SLE patients.
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