據(jù)12月21日,，每日科學(xué)報(bào)道,，調(diào)節(jié)性T細(xì)胞（Treg細(xì)胞）,，是人體免疫系統(tǒng)組成的一部分,，下調(diào)其他免疫細(xì)胞的活性以防止出現(xiàn)自身免疫性疾病或過(guò)敏反應(yīng)。德國(guó)癌癥研究中心（DKFZ）的科學(xué)家目前已發(fā)現(xiàn)在免疫細(xì)胞中被Treg細(xì)胞阻斷的激活步驟,。鑒于Treg細(xì)胞也能抑制機(jī)體對(duì)癌癥的免疫防御,，DKFZ的研究人員獲得的這些發(fā)現(xiàn)對(duì)于開(kāi)發(fā)更有效的癌癥療法是非常重要的。
人體自身的免疫系統(tǒng)不會(huì)過(guò)激反應(yīng),，這是至關(guān)重要的,。如果其關(guān)鍵成員，輔助性T細(xì)胞失控了,，將導(dǎo)致自身免疫性疾病或過(guò)敏,。免疫系統(tǒng)如果對(duì)傳染性病原體反應(yīng)過(guò)激，甚至可能直接損害器官和組織,。
稱為調(diào)節(jié)性T細(xì)胞（Treg細(xì)胞）的一種免疫細(xì)胞,，確保了免疫反應(yīng)以協(xié)調(diào)的方式發(fā)生。它們下調(diào)輔助T細(xì)胞的分裂活動(dòng)并減少它們產(chǎn)生的免疫介質(zhì),。"這是通過(guò)Treg細(xì)胞和輔助T細(xì)胞的直接接觸達(dá)到的",，DKFZ的Peter Krammer教授說(shuō)，"但是到目前為止我們?nèi)圆磺宄@種接觸作用究竟在輔助性細(xì)胞中引發(fā)了什么,。"研究人員的假設(shè)是,，與Treg細(xì)胞的接觸影響了復(fù)雜信號(hào)級(jí)聯(lián)反應(yīng)中某些特定的步驟，結(jié)果導(dǎo)致了輔助性T細(xì)胞的激活,。
如果T細(xì)胞受體,，一種位于輔助性T細(xì)胞表面的傳感器分子，感應(yīng)到外援蛋白或受損的蛋白分子,，這將觸發(fā)一個(gè)生化激活反應(yīng)的級(jí)聯(lián)反應(yīng),。在信號(hào)級(jí)聯(lián)的終末，免疫攻擊所需的基因?qū)⒃谳o助性細(xì)胞的細(xì)胞核內(nèi)開(kāi)始轉(zhuǎn)錄,。
聯(lián)合數(shù)個(gè)德國(guó)科研機(jī)構(gòu)的研究人員,，Peter Krammer、Angelika Schmidt及其同事們目前已比較了接觸或未接觸Treg細(xì)胞時(shí)輔助性細(xì)胞內(nèi)的信號(hào)級(jí)聯(lián)反應(yīng),。免疫學(xué)家發(fā)現(xiàn),，在培養(yǎng)皿中兩種細(xì)胞短暫的接觸就足以抑制輔助性T細(xì)胞。Treg細(xì)胞接觸后，典型的釋放鈣離子進(jìn)入輔助性細(xì)胞胞漿這一過(guò)程并沒(méi)有發(fā)生,。結(jié)果,，兩個(gè)很重要的轉(zhuǎn)錄因子，NFkappaB和NFAT,，不再起作用,。它們通常會(huì)激活免疫介質(zhì)的基因，以提醒免疫系統(tǒng),。
"Treg細(xì)胞的反應(yīng)模式對(duì)于癌癥藥物具有重要的意義,。我們很多同事都發(fā)現(xiàn)，在各種癌細(xì)胞中,，Treg細(xì)胞能夠下調(diào)對(duì)腫瘤的免疫反應(yīng),，使轉(zhuǎn)化細(xì)胞能夠逃脫免疫防御，這為癌癥的形成和擴(kuò)散做出了貢獻(xiàn),。因此,，我們正尋找一些方法，重新激活這些受抑制的輔助性細(xì)胞",，Krammer說(shuō),，解釋了他的工作目標(biāo)。為了開(kāi)發(fā)對(duì)抗癌癥的免疫療法,，了解Treg細(xì)胞是如何工作同樣至關(guān)重要,。研究人員目前正試圖阻止Treg細(xì)胞對(duì)培養(yǎng)皿中已激活的抗癌免疫細(xì)胞的即刻再次抑制作用。（生物谷bioon.com）
doi:10.1126/scisignal.2002179
Human Regulatory T Cells Rapidly Suppress T Cell Receptor-Induced Ca2 , NF- B, and NFAT Signaling in Conventional T Cells
A. Schmidt, N. Oberle, E.-M. Weiss, D. Vobis, S. Frischbutter, R. Baumgrass, C. S. Falk, M. Haag, B. Brugger, H. Lin, G. W. Mayr, P. Reichardt, M. Gunzer, E. Suri-Payer, P. H. Krammer.
Abstract: CD4+CD25hiFoxp3+ regulatory T cells (Tregs) are critical mediators of self-tolerance, which is crucial for the prevention of autoimmune disease, but Tregs can also inhibit antitumor immunity. Tregs inhibit the proliferation of CD4+CD25– conventional T cells (Tcons), as well as the ability of these cells to produce effector cytokines; however, the molecular mechanism of suppression remains unclear. Here, we showed that human Tregs rapidly suppressed the release of calcium ions (Ca2+) from intracellular stores in response to T cell receptor (TCR) activation in Tcons. The inhibition of Ca2+ signaling resulted in decreased dephosphorylation, and thus decreased activation, of the transcription factor nuclear factor of activated T cells 1 (NFAT1) and reduced the activation of nuclear factor B (NF- B). In contrast, Ca2+-independent events in Tcons, such as TCR-proximal signaling and activation of the transcription factor activator protein 1 (AP-1), were not affected during coculture with Tregs. Despite suppressing intracellular Ca2+mobilization, coculture with Tregs did not block the generation of inositol 1,4,5-trisphosphate in TCR-stimulated Tcons. The Treg-induced suppression of the activity of NFAT and NF- B and of the expression of the gene encoding the cytokine interleukin-2 was reversed in Tcons by increasing the concentration of intracellular Ca2+. Our results elucidate a previously unrecognized and rapid mechanism of Treg-mediated suppression. This increased understanding of Treg function may be exploited to generate possible therapies for the treatment of autoimmune diseases and cancer.
