The Calcium Sensors STIM1 and STIM2 Control B Cell Regulatory Function through Interleukin-10 Production
The Calcium Sensors STIM1 and STIM2 Control B Cell Regulatory Function through Interleukin-10 Production
复制标题
DOI：
10.1016/j.immuni.2011.03.016
复制
发表时间：
2011-05-27
期刊：
影响因子：
32.4
通讯作者：
Baba, Yoshihiro
中科院分区：
文献类型：
--
作者：
Matsumoto, Masanori;Fujii, Yoko;Baba, Yoshihiro
免疫细胞中主要的 Ca(2+) 进入途径是钙池操纵的 Ca(2+) (SOC) 内流，该内流是由内质网 (ER) 中 Ca(2+) 的消耗所触发的。然而，它在 B 细胞中的生理作用仍然难以捉摸。在这里，我们表明 ER 钙传感器 STIM1 和 STIM2 诱导的 SOC 流入对于 B 细胞调节功能至关重要。小鼠 B 细胞特异性删除 STIM1 和 STIM2 会导致 B 细胞受体 (BCR) 诱导的 SOC 流入和增殖出现严重缺陷。然而，B 细胞发育和抗体反应不受影响。值得注意的是，缺乏两种 STIM 蛋白的 B 细胞无法产生抗炎细胞因子 IL-10，因为 BCR 刺激后活化 T 细胞核因子 (NFAT) 的激活有缺陷。这导致实验性自身免疫性脑脊髓炎（多发性硬化症小鼠模型）的恶化。我们的数据表明 STIM 依赖性 SOC 流入是限制自身免疫所需的 B 细胞调节功能的关键信号。
A chief Ca(2+) entry pathway in immune cells is store-operated Ca(2+) (SOC) influx, which is triggered by depletion of Ca(2+) from the endoplasmic reticulum (ER). However, its physiological role in B cells remains elusive. Here, we show that ER calcium sensors STIM1- and STIM2-induced SOC influx is critical for B cell regulatory function. B cell-specific deletion of STIM1 and STIM2 in mice caused a profound defect in B cell receptor (BCR)-induced SOC influx and proliferation. However, B cell development and antibody responses were unaffected. Remarkably, B cells lacking both STIM proteins failed to produce the anti-inflammatory cytokine IL-10 because of defective activation of nuclear factor of activated T cells (NFAT) after BCR stimulation. This resulted in exacerbation of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our data establish STIM-dependent SOC influx as a key signal for B cell regulatory function required to limit autoimmunity.