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Aug 15, 2014

Critical Immune System Control Mechanism Discovered

  • Researchers at the Salk Institute say they have discovered a key control mechanism on regulatory T cells (Tregs) that determine if they send a halt signal to killer T cells during a pathogenic attack on the immune system. The new research (“Function of a Foxp3 cis-Element in Protecting Regulatory T Cell Identity”), published in Cell, could help develop treatments for autoimmune disorders as well as some types of cancer, according to the scientists.

    When faced with pathogens, the immune system summons a swarm of cells made up of Tregs and killer T cells. Basically, Tregs tell killer T cells to halt “their attack” when invaders are cleared. Without this signal killer T cells continue their activities and turn on the body, causing inflammation and autoimmune disorders such as allergies, asthma, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes.

    “We discovered a mechanism responsible for stabilizing the cells that maintain immune system balance,” said senior author Ye Zheng, Salk Ph.D., assistant professor and holder of the Hearst Foundation Developmental Chair. “The immune system plays a huge role in chronic inflammation and if we can better understand the immune system, we can start to understand and treat many diseases.”

    Tregs are like the surveillance system of the immune response, noted Dr. Zheng, adding that this surveillance system is “key to healthy immune reactions, but it can be kicked into overdrive or turned entirely off.”  For about a decade, researchers knew that the key to Tregs' peacekeeping ability was the Foxp3 gene, but they weren't sure how exactly it worked. Scientists also knew that under certain conditions, Tregs can go rogue: They transform into killer T cells and join in the immune system battle. This change means that they lose the ability to send a “halt” signal and add to inflammation.

    In the new paper, Dr. Zheng's lab reports that a particular genetic sequence in Foxp3 is solely responsible for the stability of a Treg. If they removed the sequence, dubbed CNS2, Tregs became unstable and often morphed into killer T cells—the type of cell they are supposed to be controlling—resulting in autoimmune disease in animal models.

    “Conserved noncoding sequence 2 (CNS2), a CpG-rich Foxp3 intronic cis-element specifically demethylated in mature Tregs, helps maintain immune homeostasis and limit autoimmune disease development by protecting Treg identity in response to signals that shape mature Treg functions and drive their initial differentiation,” wrote the researchers. “In activated Tregs, CNS2 helps protect Foxp3 expression from destabilizing cytokine conditions by sensing TCR/NFAT activation, which facilitates the interaction between CNS2 and Foxp3 promoter. Thus, epigenetically marked cis-elements can protect cell identity by sensing key environmental cues central to both cell identity formation and functional plasticity without interfering with initial cell differentiation.”

    “Foxp3 safeguards Treg to not become anything else,” continued Dr. Zheng. “Previously, very little was known on how Foxp3 did this. We discovered the area of the Foxp3 gene that determines the stability of Tregs and keeps the immune system balanced.”

    He pointed out that recent new drugs on the market or in clinical trials are attempting to disable Tregs in tumors to help the body's own immune system fight cancer. He believes this new work provides a target for future cancer drugs as well as autoimmune treatments.

    “Now we can try to target this region on Foxp3 to either enhance or reduce the impact of Tregs for treatment of autoimmune disease or cancer, respectively,” he said.


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