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Nature:中国科学家发现人体免疫系统工作新机制

近日,国际权威学术期刊《Nature》在线发表了中科院上海生科院生物化学与细胞生物学研究所/国家蛋白质科学中心(上海)许琛琦研究员领导的研究组的最新成果,首次证明钙离子能改变脂分子功能来帮助T淋巴细胞活化,提高T细胞对外来抗原的敏感性,从而帮助机体清除病原体。

这项新成果对治疗自身免疫病、慢性病毒感染、肿瘤等多种与T细胞相关的疾病有很好的指导意义。该论文也是新成立的国家蛋白质科学中心(上海)的第一篇学术论文。

人体的免疫系统复杂而精确,其中T细胞是一种关键的功能细胞,是保证机体健康的基础,与肿瘤、艾滋病、免疫缺陷症等疾病直接相关。艾滋病病毒正是通过感染T细胞从而破坏免疫系统并使人致病。

T细胞发挥功能的基础是识别外来抗原,这项功能由T细胞抗原受体(TCR)来行使。每一个T细胞表面都有几千个TCR,TCR的周围是脂质分子,它们通过静电力将TCR的活化位点屏蔽起来,保证它们在没有抗原的时候不会活化,接受抗原刺激后则快速活化。

钙离子在细胞内担任非常重要的“信号使者”角色。T细胞被抗原活化后,细胞外的钙离子会通过钙离子通道流入细胞内,细胞内钙离子浓度会在数秒之内提高10倍,并维持几个小时。这些钙离子能够直接结合TCR周围的脂质分子,中和它们的负电荷,从而解除脂质分子对TCR活化位点的屏蔽,帮助TCR活化,将比较弱的抗原刺激信号放大,使得T细胞获得完全的效应功能。这种机制大大提高了T细胞对抗原的敏感性。

美国科学院院士,斯坦福大学医学院免疫、移植与感染研究所所长、著名免疫学家Mark Davis教授指出,这项工作令人激动,揭示了钙离子对TCR活化及其T细胞生理功能的重要作用,解决了T细胞活化的一个关键性问题。

更多了解:

Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids

XiaoshanShi,YunchenBi,WeiYang,XingdongGuo,YanJiang,ChanjuanWan,LunyiLi,YibingBai,JunGuo,YujuanWang,XiangjunChen,BoWu,HongbinSun,WanliLiu,JunfengWang&ChenqiXu

Ionic protein–lipid interactions are critical for the structure and function of membrane receptors, ion channels, integrins and many other proteins1, 2, 3, 4, 5, 6, 7. However, the regulatory mechanism of these interactions is largely unknown. Here we show that Ca2+ can bind directly to anionic phospholipids and thus modulate membrane protein function. The activation of T-cell antigen receptor–CD3 complex (TCR), a key membrane receptor for adaptive immunity, is regulated by ionic interactions between positively charged CD3ε/ζ cytoplasmic domains (CD3CD) and negatively charged phospholipids in the plasma membrane1, 8, 9, 10. Crucial tyrosines are buried in the membrane and are largely protected from phosphorylation in resting T cells. It is not clear how CD3CD dissociates from the membrane in antigen-stimulated T cells. The antigen engagement of even a single TCR triggers a Ca2+ influx11 and TCR-proximal Ca2+ concentration is higher than the average cytosolic Ca2+ concentration12. Our biochemical, live-cell fluorescence resonance energy transfer and NMR experiments showed that an increase in Ca2+ concentration induced the dissociation of CD3CD from the membrane and the solvent exposure of tyrosine residues. As a consequence, CD3 tyrosine phosphorylation was significantly enhanced by Ca2+ influx. Moreover, when compared with wild-type cells, Ca2+ channel-deficient T cells had substantially lower levels of CD3 phosphorylation after stimulation. The effect of Ca2+ on facilitating CD3 phosphorylation is primarily due to the charge of this ion, as demonstrated by the fact that replacing Ca2+ with the non-physiological ion Sr2+ resulted in the same feedback effect. Finally, 31P NMR spectroscopy showed that Ca2+ bound to the phosphate group in anionic phospholipids at physiological concentrations, thus neutralizing the negative charge of phospholipids. Rather than initiating CD3 phosphorylation, this regulatory pathway of Ca2+ has a positive feedback effect on amplifying and sustaining CD3 phosphorylation and should enhance T-cell sensitivity to foreign antigens. Our study thus provides a new regulatory mechanism of Ca2+ to T-cell activation involving direct lipid manipulation.


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