When a threat to the body presents itself, previously quiet CD8+ T cells become cytotoxic, proliferating and producing enzymes poised to lyse their enemies.
當對身體的威脅出現時，先前休止的CD8+T細胞，變成具細胞毒素性，增殖並產生準備裂解敵人的酵素。
Once the immune cells vanquish their foes, whether they are infected cells or altered cancerous ones, most of the cytotoxic T cell soldiers die off, leaving a few behind to turn into memory T cells that will protect their host from future assaults.
一旦免疫細胞戰勝其敵人，無論是被感染的細胞，或是變異的癌細胞，大多數具細胞毒素性的T細胞士兵陣亡，留下少數轉變成，能保護其主人免遭未來之襲擊的記憶T細胞。
Memory T cells are an important part of the adaptive immune response because they respond to threats more quickly than naïve T cells. When faced with a familiar antigen, they rapidly transform into effector cytotoxic T cells. However, scientists are still working out the details of how memory T cells form.
記憶T細胞是適應性免疫反應的一個重要部分，因為它們比初始T細胞更快，對威脅作出反應。當面對熟悉的抗原時，它們迅速轉變成，起作用之具細胞毒素性的T細胞。不過，科學家們仍在瞭解，記憶T細胞如何形成的細節。
Immunologists Leonid Pobezinsky and Elena Pobezinskaya from the University of Massachusetts Amherst recently examined this question in the context of cancer and published their work in Nature Communications.
來自美國馬薩諸塞大學阿默斯特分校的免疫學家，Leonid Pobezinsky及 Elena Pobezinskaya，最近在癌腫背景下，探究了此問題，且在《自然•通訊》期刊，發表了他們的研究。
Pobezinsky’s group previously found that a family of noncoding microRNAs (miRNAs) called let-7 are important for the formation of cytotoxic T cells. When expressed in non-immune cells, these miRNAs are well-documented tumor suppressors that directly target the mRNA of genes involved in cell cycle regulation.
先前，Pobezinsky的團隊發現，一個被稱為let-7之非指定遺傳碼的microRNA(miRNA)家族，對具細胞毒素性T細胞的形成是重要的。當在非免疫細胞中，作出表現時。此些miRNA是直接鎖定，涉及細胞週期調節基因之mRNA，證據充分的腫瘤抑制因子。
They are also highly expressed in naïve T cells, but are downregulated after CD8+ T cell activation. In a petri dish, the researchers saw that the absence of let-7 opened the door for proliferation and differentiation into cytotoxic T cells that actively killed tumor cells.
在初始T細胞中，它們也高度作出表現。不過，在CD8+ T細胞活化後，下調。在培養皿中，此些研究人員發現，let-7的缺乏為增殖及分化成，積極殺死腫瘤細胞的具細胞毒素性T細胞，開啟了途徑。
In the new study, the researchers analyzed how the miRNA family affected T cell formation in vivo by transferring CD8+ T cells expressing various levels of let-7 into mice bearing melanoma tumors.
在該項新研究中，藉由將表現出不同水平之let-7的CD8+ T細胞，轉移到罹患黑色素瘤的小鼠體內。此些研究人員分析了，miRNA家族於體內，如何影響T細胞形成。
In this case, let-7 overexpression promoted memory T cell formation and slowed tumor growth, while cells lacking the miRNAs failed to control the tumors. These findings were in direct opposition to the research team’s in vitro work. “We really were shocked to see that,” said Pobezinsky.
在此事例中，let-7的過度表現促進了記憶T細胞形成，且減緩了腫瘤的生長，而缺乏miRNA的細胞無法控制腫瘤。此些發現與該研究團隊，於體外的研究，直接對立。Pobezinsky宣稱：「看到那，我們真的很震驚。」
The researchers think that the formation of a memory cell pool was key to these differences in the mice. To avoid an overreactive response that harms healthy cells, cytotoxic T lymphocytes express inhibitory surface receptors, or immune checkpoint molecules.
此些研究人員認為，記憶細胞庫的形成是於小鼠中，此些差異的關鍵。為了避免損傷健康細胞的過度反應，具細胞毒素性的T淋巴細胞，表現出抑制性的表面受體。也就是，免疫檢查點分子。
Tumors can avoid attack by binding to these receptors, which drives the T cells to a dysfunctional state called exhaustion. In contrast, memory T cells are invisible to tumors because they lack certain inhibitory surface receptors.
腫瘤能藉由與此些驅動T細胞進入一種，被稱為枯竭之功能失調狀態的受體結合，來避免攻擊。相較下，記憶T細胞對腫瘤，是看不見的。因為，它們缺乏某些抑制的表面受體。
“Mother Nature doesn't want you to inactivate memory cells, which are generated after an immune response, because you want to keep them for the rest of your life,” said Pobezinsky.
Pobezinsky宣稱：「大自然不希望人們鈍化，免疫反應後產生的記憶細胞。因為，人們需要保有它們供餘生之用。」
When the scientists transferred T cells with low let-7 levels into the melanoma mouse model, the cancer cells likely took advantage of the cytotoxic T cells’ inhibitory receptors, inducing exhaustion.
當此些科學家將低let-7水平的T細胞，轉移到黑色素瘤小鼠模型中時。癌細胞很可能利用了，具細胞毒素性T細胞的抑制性受體，而導致T細胞枯竭。
The T cells expressing let-7 escaped this fate and instead formed memory cells that kept producing functional cytotoxic T cells in response to the cancer antigens. “We had 70-80 percent tumor-free mice, which is unheard of, especially expressing just one miRNA,” said Pobezinsky.
使let-7作出表現的T細胞逃脫了此命運，在對癌腫抗原作出反應上，反而形成不斷產生功能性之具細胞毒素性T細胞的記憶細胞。Pobezinsky宣稱：「我們獲得了70-80%呈現無腫瘤的小鼠，這是未曾聽聞的，特別是僅使一種miRNA作出表現。」
To understand the cellular mechanisms involved in memory formation, the researchers compared the transcriptomes of T cells expressing let-7 to those that did not.
為了瞭解於記憶形成中，涉及的諸多細胞機制。此些研究人員進行了，使let-7作出表現與那些沒使let-7作出表現之T細胞轉錄體(是個體或細胞群中，包括指定遺傳碼及非指定遺傳碼之所有RNA轉錄的集合)的比較。
They found significant changes in the cells with let-7, including the inhibition of pathways important for reactive oxygen species (ROS) production, which shifts CD8+ T cells toward the memory phenotype.
他們發現了，在具有let-7之細胞中的顯著變化，包括使CD8+ T細胞朝記憶表現型改變之抑制活性氧類(ROS)產生的重要途徑。
To test this finding, the researchers treated let-7 deficient T cells during early activation with a drug that inhibits a ROS production pathway. Once those cells were injected into tumor-bearing mice, they behaved like let-7-expressing T cells—they reduced tumor burdens and prolonged survival.
為了驗證上述發現，此些研究人員，在初期活化期間，使用抑制一種ROS產生途徑的藥物，處理了let-7有缺陷的T細胞。一旦那些細胞被注射到具有腫瘤的小鼠中，它們表現如同let-7作出表現的T細胞，減少了腫瘤負荷，且延長了存活期。
Pobezinsky’s research team is currently investigating how let-7 controls the pathways involved in ROS production. In the future, the researchers see potential in administering let-7 miRNA as an immunotherapy to control tumor growth because of its role as a tumor suppressor and its influence on memory T cell formation.
目前，Pobezinsky的研究團隊正在調查研究，let-7如何控制涉及ROS產生的途徑。此些研究人員看到了，於未來，使用let-7 miRNA作為免疫療法，來控制腫瘤生長的潛力。因為，它作為腫瘤抑制因子的作用，及其對記憶T細胞形成的影響。
“The authors perform a variety of elegant immunological and transcriptional experimentation that supports that forced overexpression of let-7 may be one strategy to tip the balance in favor of the immune system in the fight against cancer,” Ingunn Stromnes, a cancer immunologist at the University of Minnesota who was not involved in this study, said in an email. “Understanding how to translate this to the human setting will be of interest, and with the explosion in gene engineering technologies, overexpressing let-7 in non-activated T cells may indeed be feasible.”
美國明尼蘇達大學，未涉及該項研究的癌腫免疫學家，Ingunn Stromnes在一封電子郵件中宣稱：「在對抗癌腫上，此些撰文者們進行了，各種精確之免疫學上及轉錄上的實驗，來支持let-7被迫過度表現，可能是一種打翻平衡有利於免疫系統之策略。瞭解如何將其轉譯到人類環境，會是令人感興趣的。因此，隨著基因工程技術的爆發，在非活化之T細胞中，過度使let-7作出表現，可能確實是可行的。
網址：https://www.the-scientist.com/news/a-microrna-family-drives-the-t-cell-response-in-cancer-71474
翻譯：許東榮
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