12月3日凌晨2時(shí),，國際權(quán)威學(xué)術(shù)期刊 Nature（《自然》）在線發(fā)表了中科院上海生科院生物化學(xué)與細(xì)胞生物學(xué)研究所/國家蛋白質(zhì)科學(xué)中心（上海）許琛琦研究員領(lǐng)導(dǎo)的研究組的最新成果，首次證明：鈣離子能夠改變脂分子功能來幫助T淋巴細(xì)胞活化,，提高T淋巴細(xì)胞對外來抗原的敏感性,，從而幫助機(jī)體清除病原體。該論文也是新成立的國家蛋白質(zhì)科學(xué)中心（上海）的第一篇學(xué)術(shù)論文,。
提高免疫力,，預(yù)防疾病是人們的迫切需要。人體的免疫系統(tǒng)復(fù)雜而精確,，其中T淋巴細(xì)胞（簡稱T細(xì)胞）是一種關(guān)鍵的功能細(xì)胞,，是保證機(jī)體健康的基礎(chǔ)，與多種疾病直接相關(guān)（如腫瘤,、艾滋病,、免疫缺陷癥,、自身免疫病等）。艾滋病毒正是通過感染T細(xì)胞從而破壞人的免疫系統(tǒng)并使人致病,。
T細(xì)胞發(fā)揮功能的基礎(chǔ)是識別外來的抗原,，這項(xiàng)功能由T細(xì)胞抗原受體（TCR）來行使。每一個(gè)T細(xì)胞表面都有幾千個(gè)TCR,，像哨兵一樣擔(dān)任警戒任務(wù),；TCR的周圍是脂質(zhì)分子，它們通過靜電力將TCR的活化位點(diǎn)屏蔽起來,，保證它們在沒有抗原的時(shí)候不會活化,，接受抗原刺激后則快速活化，由此調(diào)控著“哨兵”的戰(zhàn)斗力,?？乖せ頣CR是T細(xì)胞免疫反應(yīng)關(guān)鍵性的一步。經(jīng)過長期的進(jìn)化,，TCR能夠監(jiān)測到非常微量的抗原信號,，從而保證機(jī)體能高效以及快速地清除入侵的病原體。TCR如何被抗原活化以及T細(xì)胞如何獲得這么高的抗原敏感性還是懸而未決的問題,。
鈣離子是人體內(nèi)必需的金屬離子,，除了組成骨骼和牙齒外，還在細(xì)胞內(nèi)擔(dān)任非常重要的“信號使者”的角色,。T細(xì)胞被抗原活化后,，細(xì)胞外的鈣離子會通過鈣離子通道流入細(xì)胞內(nèi)，細(xì)胞內(nèi)鈣離子濃度會在數(shù)秒之內(nèi)提高10倍,，并維持幾個(gè)小時(shí),。這些鈣離子能夠直接結(jié)合TCR周圍的脂質(zhì)分子，中和它們的負(fù)電荷,，從而解除脂質(zhì)分子對TCR活化位點(diǎn)的屏蔽,，幫助TCR活化，將比較弱的抗原刺激信號放大,，使得T細(xì)胞獲得完全的效應(yīng)功能,。這種機(jī)制大大提高了T細(xì)胞對抗原的敏感性。
美國科學(xué)院院士,，斯坦福大學(xué)醫(yī)學(xué)院免疫,、移植與感染研究所所長、著名免疫學(xué)家Mark Davis教授指出這項(xiàng)工作非常漂亮并令人激動(dòng),，揭示了鈣離子對TCR活化及其T細(xì)胞生理功能的重要作用,，解決了T細(xì)胞活化的一個(gè)關(guān)鍵性問題。
中科院上海巴斯德所所長孫兵教授指出鈣信號通路是多種疾病的藥物靶點(diǎn),。這項(xiàng)新的成果對治療多種T細(xì)胞相關(guān)的疾?。ㄈ缱陨砻庖卟。圆《靖腥?，腫瘤等）有很好的指導(dǎo)意義,。
該工作與中科院強(qiáng)磁場科學(xué)中心王俊峰研究組共同完成，清華大學(xué)劉萬里研究組參與了合作研究,。工作受到了科技部,、國家自然科學(xué)基金委、中國科學(xué)院以及上海市科委的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
doi:10.1038/nature11699
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Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids
Xiaoshan Shi, Yunchen Bi,， Wei Yang, Xingdong Guo，Yan Jiang,， Chanjuan Wan,， Lunyi Li， Yibing Bai,， Jun Guo,， Yujuan Wang， Xiangjun Chen,， Bo Wu,， Hongbin Sun， Wanli Liu,， Junfeng Wang,， Chenqi Xu
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.
