Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength
Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength
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DOI：
10.1073/pnas.1323557111
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发表时间：
2014-08-12
影响因子：
11.1
通讯作者：
Fukada, Toshiyuki
中科院分区：
文献类型：
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作者：
Hojyo, Shintaro;Miyai, Tomohiro;Fukada, Toshiyuki
体液免疫反应又称抗体介导的免疫反应，是主要的适应性免疫系统之一。必需微量营养素锌（Zn）被认为可以调节适应性免疫反应，而锌稳态失调会导致免疫缺陷。然而，这种锌介导的调节的分子机制在很大程度上是未知的。本研究表明，锌转运蛋白SLC39A10/ZIP10在b细胞抗原受体（BCR）信号转导中起重要作用。体内成熟B细胞zip10缺乏可减弱t细胞依赖性和非依赖性免疫反应。由于BCR信号失调，zip10缺陷的成熟B细胞在BCR交联反应中增殖不良。干扰的信号被发现是由CD45R磷酸酶活性的降低和随后的LYN （BCR信号中必不可少的蛋白激酶）的过度激活引发的。我们的数据表明，ZIP10作为CD45R的正调控因子调节BCR信号强度，从而为BCR信号在体液免疫应答中设置一个阈值。
The humoral immune response, also called the antibody-mediated immune response, is one of the main adaptive immune systems. The essential micronutrient zinc (Zn) is known to modulate adaptive immune responses, and dysregulated Zn homeostasis leads to immunodeficiency. However, the molecular mechanisms underlying this Zn-mediated modulation are largely unknown. Here, we show that the Zn transporter SLC39A10/ZIP10 plays an important role in B-cell antigen receptor (BCR) signal transduction. Zip10-deficiency in mature B cells attenuated both T-cell-dependent and -independent immune responses in vivo. The Zip10-deficient mature B cells proliferated poorly in response to BCR cross-linking, as a result of dysregulated BCR signaling. The perturbed signaling was found to be triggered by a reduction in CD45R phosphatase activity and consequent hyperactivation of LYN, an essential protein kinase in BCR signaling. Our data suggest that ZIP10 functions as a positive regulator of CD45R to modulate the BCR signal strength, thereby setting a threshold for BCR signaling in humoral immune responses.