Immune-regulating pathway may be target for MS and other diseases
A signaling molecule called erythropoietin (EPO) plays a key role in allowing the immune system to distinguish the body’s own cells from foreign threats, a new study shows.
The findings could lead to new treatments for diseases like multiple sclerosis (MS), in which the immune system inadvertently starts to attack the body’s own healthy cells. Researchers also believe that this newly discovered molecular mechanism could be targeted to unleash the immune system’s ability to destroy cancers.
“This mechanism is not only required for physiological tolerance that prevents autoimmune disease, but it is often hijacked by cancers and probably some infectious pathogens, too, enabling their ability to evade immune attack,” Edgar Engleman, MD, PhD, a professor at Stanford University and co-author of the study, said in a university press release.
“I believe that manipulation of this pathway will eventually be used to treat a wide range of diseases,” Engleman added.
The study, “Erythropoietin receptor on cDC1s dictates immune tolerance,” was published in Nature. The work was funded by the National Institutes of Health (NIH).
The immune system essentially has two primary functions: it leaves the body’s healthy cells alone, and it targets and attacks everything else. The ability of the immune system to distinguish between self and non-self is known as immune tolerance. T-cells are a class of immune cells that play key roles in maintaining tolerance. Some T-cells are inflammatory and are designed to attack, whereas others known as regulatory T-cells (Tregs) are anti-inflammatory, preventing attacks against healthy cells.
Scientists who helped discover Tregs were awarded this year’s Nobel Prize in physiology or medicine. However, although it has been well-established how Tregs function once they’re activated, the mechanisms that govern their activation aren’t fully understood.
Type 1 conventional dendritic cells (cDC1s) are another type of immune cell that act as the body’s crime scene investigators, gathering up bits of dead cells and molecular debris and presenting them to T-cells. The interaction between T-cells and cDC1s can either cause activation of inflammatory T-cells or anti-inflammatory Tregs — presumably because of some difference in the molecular activity of the cDC1s. But until now, it was not known exactly what that difference could be.
“The Nobel prize was awarded for identifying regulatory T cells, or Tregs, and their role in immune tolerance, without knowing what triggers them,” Engleman said. “Now we know the EPO signaling pathway in dendritic cells is what triggers them, and I’m more than a little excited about it. … We not only discovered this mechanism, but we also learned how it can be turned on and off.”
EPO is a signaling molecule that’s long been known to help control the growth of red blood cells, but the new data show that it also plays key roles in controlling how cDC1s activate T-cells.
“It’s fascinating that this fundamental mechanism took so long to discover,” Engleman said. “It’s even possible that this is the primary function of EPO, and that its effect on red blood cell formation is secondary. There is no doubt these findings will light many research fires.”
Working in a mouse model, the researchers found that EPO binds to protein receptors on cDC1s, triggering these cells to send signals that activate Tregs. But when EPO signaling is blocked, the cDC1s instead promote the activity of pro-inflammatory T-cells.
“What was quite a surprise to me is that when you remove or block the EPO receptor on the dendritic cells, you don’t just block the development of tolerance,” Engleman said. “Instead, you have now converted these dendritic cells into super stimulators, or powerful activators of immune response.”
The scientists believe this molecular pathway could be targeted to treat a variety of diseases. Activating this pathway could help reduce unnecessary immune activity in diseases like MS, while blocking this pathway could help the immune system better fight off infections or cancers. Altogether, these data provide “a compelling rationale for developing immunotherapies that target [EPO receptor proteins] on cDC1s, including agonists [activators] to induce tolerance in transplantation or autoimmune disease and antagonists [inhibitors] to break tolerance and promote immunity to infection and tumours,” the researchers concluded.
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