生物谷報道：早在14年前,，研究人員首次發(fā)現(xiàn)了Lag-3基因（淋巴細胞活化基因-3），但是一直以來卻不知道它的功能?，F(xiàn)在St. Jude Children’s Research Hospital和Johns Hopkins Kimmel Cancer Center的研究人員發(fā)現(xiàn)Lag-3基因能夠防止免疫系統(tǒng)反應變得不受控制,，即具有“剎車閘”的作用,。這些研究結果公布在10月的Immunity期刊上。

Lag-3蛋白位于調節(jié)性T細胞的表面,，而調節(jié)性T細胞能夠干擾效應T細胞攻擊身體中的特定靶標（如癌細胞和微生物）的活動,。

研究人員證明，當缺失Lag-3基因時,，調節(jié)T細胞控制效應T細胞攻擊的能力會被消除,。效應T細胞和調節(jié)T細胞都來源于CD+T淋病細胞。當免疫系統(tǒng)發(fā)生反應時,，一些CD+4細胞中的Lag-3基因就被激活,，并且這些細胞會轉變成調節(jié)性T細胞，因此成為其它準備攻擊的CD4+T細胞的“剎車”,。

在小鼠試驗中,，研究人員首先證明調節(jié)性T細胞能夠保護有機體不受效應T細胞發(fā)動的大規(guī)模致死性的免疫系統(tǒng)的攻擊。接著,，研究組運用DNA芯片確定了轉變成調節(jié)T細胞的細胞中被活化的基因,。研究人員發(fā)現(xiàn)Lag-3基因的表達水平比效應T細胞中的水平要高。然后,，研究組證明將Lag-3基因插入CD4+T細胞能夠將這些細胞變成調節(jié)性T細胞,。研究人員還進一步證明Lag-3蛋白在控制受體T細胞功能的調節(jié)性T細胞上起到一個關鍵的作用。

這項研究表明Lag-3基因的功能是控制調節(jié)性T細胞的免疫反應抑制作用,。調節(jié)性T細胞的抑制活性既能夠防止自體免疫疾病的破壞作用,，但同時也能抑制抗腫瘤效應細胞的有益活性。因此,，這項研究證明調節(jié)性T細胞在抑制免疫系統(tǒng)的抗腫瘤活性方面起到關鍵作用,。這些細胞表面的Lag-3蛋白的確定能夠促進與免疫系統(tǒng)有關的癌癥的治療。

The discovery that the Lag-3 gene acts as a brake to prevent immune system responses from running out of control solves a mystery that has puzzled researchers since the gene was discovered 14 years ago. A report on this discovery, from investigators at St. Jude Children's Research Hospital and The Johns Hopkins Kimmel Cancer Center, is published in the October issue of the journal Immunity.

The researchers solved the mystery of what Lag-3 does by showing that the gene permits so-called regulatory T cells to act as brakes on the immune system.

Regulatory T cells, which carry the Lag-3 protein on their surfaces, interfere with the action of effector T cells--the "warrior" cells that orchestrate attacks on specific targets in the body, such as cancer cells and microorganisms.

The finding could form the basis for new strategies for improving the efficacy of anti-cancer vaccines or preventing autoimmune diseases. Autoimmune diseases are those in which the immune system attacks specific tissues of a person's own body as if they were foreign matter. The researchers showed that the ability of regulatory T cells to control an attack by effector T cells is substantially prevented or eliminated in the absence of Lag-3.

Both the effector and regulatory cells arise from the same populations of cells, called CD4+ T lymphocytes, according to Dario A. A. Vignali, Ph.D., associate member of St. Jude Immunology. Vignali is senior author of the Immunity report.

The Lag-3 gene is activated in some of the CD4+ cells during an immune system response, turning them into regulatory cells that put the brakes on the activity of their fellow CD4+ T cells that are launching the attack.

"The braking action of regulatory T cells prevents the destructive effects of autoimmune diseases, such as diabetes type 1, which occurs when effector T cells mount an attack on the cells of the pancreas that produce insulin," Vignali said.

However, regulatory T cells can also block the beneficial activity of anti-tumor effector cells. This braking action could inhibit an immune system attack on cancer cells.

"This study adds to the mounting evidence that regulatory T cells play a major role in dampening the immune system's anti-tumor activity," said Charles Drake, M.D., Ph.D., assistant professor of Oncology at the Johns Hopkins Kimmel Cancer Center. "The identification of a specific molecule on the surface of these cells that we can block represents an exciting new opportunity to amplify the potency of immune-system-based cancer therapies. We're actively pursuing the best strategy to test these findings in patients."

Drake is co-author of the paper.

In mouse studies, the researchers first showed that regulatory T cells can protect against a potentially lethal, large-scale immune system attack by effector T cells that ordinarily would have caused a fatal lung disease.

Next, the team used a technique called DNA array analysis to identify which genes in the CD4+ T cells are activated in cells that develop into regulatory T cells. The investigators found that the Lag-3 gene was "expressed" (being used by the cell to make protein) to a much greater extent in regulatory T cells than in effector T cells. The team then showed that inserting the Lag-3 gene into CD4+ T cells turned them into regulatory T cells. These newly minted regulatory T cells suppressed effector T cell activity.

In addition, the researchers showed that antibodies against the Lag-3 protein block this moderating effect of regulatory T cells on the effector T cells, allowing the effector cells to continue an aggressive attack. This finding provided further evidence that Lag-3 is a key protein on regulatory T cells that controls effector T cell function.

"The tumor-specific T cells generated by some anti-cancer vaccines are not very effective because regulatory T cells block their therapeutic activity," said Creg J. Workman, Ph.D., a postdoctoral researcher in Vignali's lab and co-author of the paper. "But if researchers could block Lag-3 on regulatory T cells it might possible to free such vaccines to generate an especially aggressive attack on cancer cells." "We'd like to put that kind of control over immune function into the hands of physicians," Vignali said.