南加州大学和哈佛医学院的研究人员发现，单独的一种蛋白就能够通过改变一个“优雅的基因组舞蹈”模式就能开启和关闭
免疫系统的一个关键成分。南加州大学的华人分子和计算机生物学教授陈林（Lin Chen）是这个研究组的领头人。陈教授表示，这些结果将为了解免疫耐受性基础机制开启一扇大门。研究的结果刊登在7月28日的Cell杂志上。
由于自身免疫疾病如关节炎、过敏等，是在身体的防御应答发生在错误的时间或地点时发作的，因此免疫系统的开关是数十年来自身免疫疾病的一个重点研究课题。
这个由南加州大学和哈佛医学院组成的研究组分析了对免疫耐受性很关键的蛋白质。免疫耐受性是指弱的免疫系统和过度强悍的免疫应答之间的正常平衡。
研究组证实这种叫做NFAT（活化T细胞核因子）的蛋白质与FOXP3（一种调节性T细胞的关键因子）合作编排一种对免疫耐受性至关重要的遗传程序。
但是，同一个NFAT在与第二个蛋白质家族AP-1搭伴时却会刺激免疫应答。陈教授表示，这些发现为提出已经15年的基因表达联合控制理论提供了第一个有力的证据。
根据这个理论，一个基因的表达取决于影响它的转录因子的联合。FOXP3和NFAT就是这样两个因子，而人体含大约3000个这样的转录因子。研究人员能够确定出NFAT在与AP1联合时活化的单个基因以及在和FOXP3合作时抑制的基因。
除了阐明这种免疫机制外，Cell上的这篇文章还是向着更大的生物和医学目标——如何关闭或开启单个基因迈进的重要一步。这项研究成果也是陈教授历经14年刻苦研究获得的回报。
英文原文：
Protein Switches Immune Response
A single protein can turn on and off a key component of the immune system by changing partners in an elegant genomic dance, said researchers at USC and Harvard Medical School.
Because autoimmune diseases such as arthritis and dozens of other illnesses begin when the body’s defenses respond at the wrong time or place, the on-off mechanism for the immune system has been the subject of intense study for decades.
The USC-Harvard team studied proteins critical to immune tolerance, a term for the healthy balance between a weak immune system and an overly aggressive, indiscriminate watchdog.
Lin Chen, professor of molecular and computational biology at USC and lead co-author with Harvard’s Anjana Rao, said the team’s result would “open a big door for people to explain the fundamental mechanism of immune tolerance.”
In the July 28 issue of the science journal Cell, the USC-Harvard group shows that the protein Nuclear Factor of Activated T cells (NFAT), in collaboration with FOXP3, orchestrates a genetic program critical to maintaining immune tolerance.
But the same NFAT, paired with a second family of proteins known as AP-1, instead sharply increases immune response.
Chen said the finding offers the first strong evidence in favor of the 15-year-old “combinatorial control” theory of gene expression.
According to the theory, the specific expression of a gene depends on the combination of “transcription factors” acting on it. Transcription factors help to translate a gene’s instructions into actual proteins. FOXP3 and NFAT are two such factors; the human body contains around 3,000.
“The work provides a structural demonstration of combinatorial control of gene expression,” Chen said. “This is, in my view, the most direct demonstration that this is indeed happening in nature.”
The researchers were able to identify single genes that were activated by NFAT in combination with AP-1 and suppressed by NFAT with FOXP3.
Beyond shedding light on the immune system, the Cell paper may advance biology and medicine toward a much larger goal: how to turn single genes on or off.
“This [result] has far-reaching implications for understanding the principles of signal transduction and transcriptional networks of living cells,” Chen said.
The Cell paper, which Chen describes as spanning 14 years of laboratory work, builds on a result his group published in Nature in 1998.
Chen’s postdoctoral associates Yongqing Wu and Aidong Han are co-authors on the Cell paper. All three moved to USC recently from the University of Colorado at Boulder.
Researchers from the University of Washington in Seattle also contributed to the paper.
Funding for the team’s research came from the National Institutes of Health, the W.M. Keck Foundation, the Juvenile Diabetes Research Foundation and the American Diabetes Association.
