New Roles of Magnesium as a Regulatory Ion in Immune Responses and Cell Behavior

在哺乳动物细胞中，MAGT 1转运蛋白在细胞内游离Mg 2+水平的选择性调节中起关键作用。游离Mg ~（2+）在真核细胞中的分子功能尚未确定。我们发现，MAGT 1基因缺陷的患者具有高水平的EB病毒（EBV）和淋巴瘤的易感性。在研究来自这些患者的淋巴细胞时，我们发现MAGT 1的缺乏引起基础细胞内游离Mg 2+减少，导致NK和CD 8 + T细胞中自然杀伤激活受体NKG 2D的表达缺陷。在没有NKG 2D的情况下，针对EBV的细胞溶解反应减弱，从而揭示了真核细胞中细胞内基础游离Mg 2+的第一个特异性分子功能。此外，细胞内游离Mg 2+、NKG 2D表达和功能可通过孵育患者细胞和升高的Mg 2+水平在体外得到挽救。此外，在MAGT 1缺陷患者中，镁给药可改善NKG 2D表达和细胞溶解功能，并减少体内EBV感染的细胞。因此，我们的数据表明游离基础Mg 2+在免疫中具有重要的分子功能，并证明在人体的基本EBV抗病毒应答中需要NKG 2D细胞溶解功能。 最近在了解二价阳离子在免疫细胞中的作用方面取得的进展揭示了Mg 2+和Zn 2+的新信号功能，为未来的研究开辟了新的前景。关于Mg 2+信号传导的许多问题仍然没有答案。事实上，存在过多的表观Mg 2+转运和通道蛋白，其在人体生理学中的作用尚未在健康和患病的免疫系统中确定。在多种细胞类型中观察到Mg 2+动员，然而调节这些阳离子变化的分子机制仍然难以捉摸。技术限制，如探针灵敏度，低产电性，和其他考虑，防止这些阳离子的调节动员的精确研究。我们目前与学术和工业合作伙伴的合作旨在解决这些问题。需要进一步研究的另一个方面是对二价阳离子信号传导的各种效应物及其产生的网络的理解。除了增强基本的科学知识，回答这些问题也有重要的医学意义，特别是，但不仅是，与二价阳离子信号传导缺乏相关的免疫疾病，如XMEN病，SOCE缺乏症，甚至饮食锌2+缺乏症。30年前，钙信号抑制剂环孢霉素A（CN抑制剂）的免疫抑制能力的发现，彻底改变了器官移植。因此，发现新的Mg 2+和Zn 2+敏感性靶标或功能可以鉴定用于免疫调节的新的治疗靶标。此外，在各种病理环境中补充Mg 2+和Zn 2+的有希望的结果应该鼓励开发新的离子补充策略。此外，至少有22种已知的镁转运蛋白或通道，其中我们在T淋巴细胞上检测到至少16种。对这些转运蛋白或通道知之甚少，因此这代表了了解离子调节新的基本方面的机会。由于其他离子通道一直是良好的药物靶点，这可能会为治疗开发开辟新的领域。

The MAGT1 transporter is critically involved in the selective regulation of intracellular free Mg2+ levels in mammalian cells. The molecular functions of free Mg2+ in eukaryotic cells have not been established. We found that patients with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. In studying lymphocytes from these patients, we found that a deficiency of MAGT1 caused decreased basal intracellular free Mg2+ leading to defective expression of the natural killer activating receptor NKG2D in NK and CD8+ T cells. Without NKG2D, cytolytic responses against EBV are diminished, thereby revealing the first specific molecular function of intracellular basal free Mg2+ in eukaryotic cells. Moreover, intracellular free Mg2+, NKG2D expression and function can be rescued in vitro by incubating patient cells and elevated levels of Mg2+. Moreover, NKG2D expression and cytolytic function can be improved and EBV-infected cells reduced in vivo, in MAGT1-deficient patients by magnesium administration. Thus, our data indicate an important molecular function for free basal Mg2+ in immunity and demonstrate a requirement for NKG2D cytolytic function in an essential EBV antiviral response in humans. Recent advances in understanding the role of divalent cations in immune cells have uncovered new signaling functions for Mg2+ and Zn2+ opening new vistas for future investigation. Many questions about Mg2+ signaling are still unanswered. In fact, there are a plethora of apparent Mg2+ transport and channel proteins whose role in human physiology is not yet been determined in the healthy and diseased immune system. Mg2+ mobilization has been observed in variety of cell types, however the molecular mechanisms regulating these cation changes remain elusive. Technical limitations such as probe sensitivity, low electrogenicity, and other considerations prevent the precise study of the regulated mobilization of these cations. Our current collaborations with academic and industrial partners are directed at addressing these issues. Another aspect that require further investigation is the understanding of the various effectors of divalent cations signaling and the network(s) that they generate. Beyond enhancing the basic scientific knowledge, answering these questions have also important medical implications especially, but not only, for immune disorders associated with divalent cations signaling deficiency, such as XMEN disease, SOCE deficiency or even dietary Zn2+ deficiency. Thirty years ago, the discovery of the immunosuppressant abilities of the Ca2+ signaling inhibitors, cyclosporine A (CN inhibitor), revolutionized organ transplantation. Thus, uncovering new Mg2+ and Zn2+ sensitive targets or functions could identify new therapeutic targets for immunomodulation. Moreover, the promising results of Mg2+ and Zn2+ supplementation in various pathological settings should encourage the development of new ion supplementation strategies. Also, there are at least 22 known magnesium transporters or channels of which we have detected at least 16 on T lymphocytes. There is very little known about these transporters or channels so this represents an opportunity to understand new fundamental aspects of ion regulation. Since other ion channels have been good pharmaceutical targets, this may open up new areas for therapeutic development.