美國(guó)Pennsylvania大學(xué)醫(yī)學(xué)院科學(xué)家最近發(fā)現(xiàn)免疫細(xì)胞自我“決定”變得活躍或不活躍的機(jī)制,，這有助于癌癥，自身免疫疾病和器官移植排異的治療,。
??病理和藥學(xué)教授Gary A. Koretzky在最新的一期《Nature Immunology》上描述了T細(xì)胞是怎樣不對(duì)目標(biāo)細(xì)胞或蛋白質(zhì)發(fā)生反應(yīng)的。他們發(fā)現(xiàn),，一種叫做甘油二酯（DAGs）的脂肪酸以及一種酶是這一過(guò)程的關(guān)鍵因素,。
??免疫T淋巴細(xì)胞能識(shí)別身體的入侵者，如病毒,，細(xì)菌,，癌細(xì)胞或過(guò)敏原。正常情況下,，T細(xì)胞會(huì)由一系列復(fù)雜信號(hào)激發(fā),，最后破壞外來(lái)物。但是有些T細(xì)胞處于未激發(fā)狀態(tài),，這一過(guò)程保護(hù)免疫細(xì)胞自身和其它正常細(xì)胞不受攻擊,。
??Koretzky表示：“T淋巴細(xì)胞怎樣被激發(fā)是免疫學(xué)的主要問(wèn)題之一,。我們的研究發(fā)現(xiàn)DAGs是這些細(xì)胞對(duì)入侵者反應(yīng)的關(guān)鍵,。但是當(dāng)DAGs被甘油二酯酶（DGKs）作用后，T細(xì)胞不再對(duì)目標(biāo)作出反應(yīng),。”
??這一結(jié)果是通過(guò)研究去除了DGKs的小鼠后得出的,。雖然這些小鼠的T細(xì)胞在大部分時(shí)候很正常，但DAGs無(wú)法得到DGKs的作用,，所以T細(xì)胞會(huì)對(duì)外來(lái)抗原過(guò)度反應(yīng),。
??一種本不該引發(fā)免疫反應(yīng)的葡萄球菌毒素使小鼠T細(xì)胞發(fā)生了過(guò)度反應(yīng)。這證明是DGK的缺乏造成的,。而且T細(xì)胞制造了多于正常五倍的免疫因子,。
??過(guò)度反應(yīng)如果能被控制，就能對(duì)身體有好處,，例如T細(xì)胞能消滅癌細(xì)胞,。研究者正在繼續(xù)研究這些小鼠，看看它們是否能將癌細(xì)胞識(shí)別為入侵者并消滅它們,。
英文原文：
Penn researchers provide insights into how the immune system avoids attacking itself
A finding by University of Pennsylvania School of Medicine researchers about how immune cells “decide” to become active or inactive may have applications in fighting cancerous tumors, autoimmune diseases, and organ transplant rejection. Pathology and Laboratory Medicine Professor Gary A. Koretzky, MD, PhD, director of the Signal Transduction Program at Penn’s Abramson Family Cancer Research Institute describes, in the current issue of Nature Immunology, one way in which T cells may develop tolerance to host cells and proteins. Koretzky and colleagues found that small fatty acids called diacylglycerols (DAGs), and the enzymes that metabolize them, are critical players in the molecular pathway that leads to activity versus inactivity.
Immune cells called T lymphocytes recognize invaders in the body, such as viruses, bacteria, tumor cells, or allergens. Normally, T cells are activated by a complex series of signals that end with the destruction of the foreign substance. However, some T cells are not activated, in fact they are inactivated by a process called anergy or tolerance. This process helps prevent immune cells from attacking themselves and other normal cells and proteins.
“How T lymphocytes become activated or inactivated has been one of the major questions in the field of immunology,” says senior author Koretzky. “Our discovery shows that DAGs are critical for T-cell activation so these cells can respond to foreign invaders. However, when DAGs are chemically modified by enzymes called diacylglycerol kinases, T cells become tolerant or unresponsive to foreign substances and to self.”
The discovery was made by studying mice that had been engineered to lack diacylglycerol kinases (DGKs). Although T cells from these knock-out mice were normal in most respects the induction of tolerance was impaired. When DAGs could not be chemically altered because the DGKs were absent, the T cells were hyperreactive to foreign antigens and could not be made tolerant to host cells.
Hyperreactivity was shown when purified T cells from DGK knockout mice were stimulated by antigen in a culture dish. The failure of the T cells to become tolerant was demonstrated in experiments where mice were treated with a toxin from staphylococcal bacteria that should have induced unresponsiveness. Instead, the T cells produced about five times more of an immunity factor than did cells from normal mice.
The hyperreactive state, if controlled, might be beneficial to the body under some circumstances; for example, some T cells might be made more effective at eliminating tumors. The research team is continuing to study DGK knock-out mice to see if they are more resistant to tumors. If the hyper-reactive T cells in these mice recognize the tumor cell as a foreign invader, then the tumor might be eliminated or reduced. Conversely, if the tolerant state could be induced in a controlled manner, it might benefit individuals with autoimmune disease or help prevent rejection of transplants.
