生物谷报道：早在14年前，研究人员首次发现了Lag-3基因（淋巴细胞活化基因-3），但是一直以来却不知道它的功能。现在St. Jude Children’s Research Hospital和Johns Hopkins Kimmel Cancer Center的研究人员发现Lag-3基因能够防止免疫系统反应变得不受控制，即具有“刹车闸”的作用。这些研究结果公布在10月的Immunity期刊上。
Lag-3蛋白位于调节性T细胞的表面，而调节性T细胞能够干扰效应T细胞攻击身体中的特定靶标（如癌细胞和微生物）的活动。
研究人员证明，当缺失Lag-3基因时，调节T细胞控制效应T细胞攻击的能力会被消除。效应T细胞和调节T细胞都来源于CD+T淋病细胞。当免疫系统发生反应时，一些CD+4细胞中的Lag-3基因就被激活，并且这些细胞会转变成调节性T细胞，因此成为其它准备攻击的CD4+T细胞的“刹车”。
在小鼠试验中，研究人员首先证明调节性T细胞能够保护有机体不受效应T细胞发动的大规模致死性的免疫系统的攻击。接着，研究组运用DNA芯片确定了转变成调节T细胞的细胞中被活化的基因。研究人员发现Lag-3基因的表达水平比效应T细胞中的水平要高。然后，研究组证明将Lag-3基因插入CD4+T细胞能够将这些细胞变成调节性T细胞。研究人员还进一步证明Lag-3蛋白在控制受体T细胞功能的调节性T细胞上起到一个关键的作用。
这项研究表明Lag-3基因的功能是控制调节性T细胞的免疫反应抑制作用。调节性T细胞的抑制活性既能够防止自体免疫疾病的破坏作用，但同时也能抑制抗肿瘤效应细胞的有益活性。因此，这项研究证明调节性T细胞在抑制免疫系统的抗肿瘤活性方面起到关键作用。这些细胞表面的Lag-3蛋白的确定能够促进与免疫系统有关的癌症的治疗。
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.
