A single signaling pathway controls whether immune cells attack or befriend cells they encounter while patrolling our bodies, researchers at Stanford Medicine have found. Manipulating this pathway could allow researchers to toggle the immune response to treat many types of diseases, including cancers, autoimmune disorders and those that require organ transplants.
The research, which was conducted in mice, illuminates the mechanism of an important immune function that prevents inappropriate attacks on healthy tissue. Called peripheral immune tolerance, the key cellular players, known as regulatory T cells (or Tregs, pronounced "tee-regs"), were first described in the late 1990s in a series of discoveries that were recently recognized with the 2025 Nobel Prize in physiology or medicine.
The findings extend those of a related study published in Science by the same researchers earlier this year that described a surprising new role for a molecule known for decades to promote red blood cell formation. Now it is clear that this molecule, erythropoietin, or EPO, is the lynchpin controlling how our immune systems react to real or perceived threats — acting through immune cells called dendritic cells.
"The Nobel prize was awarded for identifying regulatory T cells, or Tregs, and their role in immune tolerance, without knowing what triggers them," said Edgar Engleman , MD, PhD, a professor of pathology. "Now we know the EPO signaling pathway in dendritic cells is what triggers them, and I'm more than a little excited about it. I believe that manipulation of this pathway will eventually be used to treat a wide range of diseases."
Engleman, a member of the Stanford Cancer Institute , is the senior author of the research , which will be published on Dec. 10. Senior research scientist Xiangyue Zhang, PhD, is the lead author of the study.
Building tolerance to oneself
The critically important building of immune tolerance to "self" is a two-step process. The first, called central immune tolerance, occurs in the bone marrow and the thymus where B cells and T cells undergo a first round of selection to eliminate or reprogram self-reactive cells before they are released into the bloodstream. The second, peripheral immune tolerance, serves as a backup to screen circulating cells that escape the first culling.
The stakes are high. An overly enthusiastic immune system that attacks healthy tissues leads to autoimmune diseases like rheumatoid arthritis, multiple sclerosis, lupus and diabetes. Conversely, a too complacent, or tolerant, response allows cancer cells to escape immune destruction, instead sending them on their way with a handshake and a pat on the back.
The immune system's response — threatening or welcoming — is governed by the Tregs, which tamp down inappropriate attack impulses of other immune cells called T and B cells.
"What had yet to be discovered is the mechanism responsible for inducing or activating Tregs in those circumstances when they are needed to suppress a dangerous immune response," Engleman said. "We not only discovered this mechanism, but we also learned how it can be turned on and off."
The researchers used an experimental approach first identified in mice and subsequently in humans in which irradiating the thymus, spleen and lymph nodes — all places in the body where immune cells hang out — kills off many of the T cells and B cells while leaving antigen-presenting cells such as dendritic cells relatively unscathed. The treatment, called total lymphoid irradiation, reprograms the recipient's immune system to permanently tolerate genetically mismatched transplanted cells or organs.
But dendritic cells don't act alone and instead recruit other immune cells, including T cells, to carry out their missions.
"All T cells, including Tregs, must first be 'presented' with a structure called an antigen that is recognized by their receptors for the cells to develop into mature T cells that either attack a target or suppress the immune response to that target," Engleman said. "Dr. Zhang and I reasoned that this process of tolerance or activation must be initiated by antigen-presenting cells."
The most powerful antigen-presenting cells in the body are called type 1 dendritic cells, which engulf dead or dying cells or pathogens and display bits of those cells like immunological fishing lures for T or B cells.
To learn how dendritic cells are involved in the development of immune tolerance, Zhang and Engleman decided to investigate whether and how the genes they express change in mice after total lymphoid irradiation. They found that the gene for the EPO receptor is expressed at much higher levels in the dendritic cells of irradiated animals, and that the levels of EPO are elevated in the animals' blood circulation.
EPO's other job
Normally this would have been a huge surprise. EPO is well known as the primary instigator of red blood cell production, and it was named for this function (erythro meaning "red" and poiein meaning "to produce"). But earlier this year, Engleman and his colleagues showed that cancer cells in immunologically tolerated, or "cold," tumors trick the immune system by making EPO and releasing it into the tumor environment where it binds to a type of immune cell called macrophages and causes these cells to become immunosuppressive. So, they knew that EPO has a second role as a master immune regulator.
When Zhang genetically manipulated the mice to remove the ability of the dendritic cells to express the EPO receptor, the animals rejected transplants of unmatched tissue after total lymphoid irradiation, showing conclusively that the EPO signaling pathway is necessary for the development of immune tolerance. But there was another intriguing finding.
"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. There is a dual opportunity to not just induce tolerance to treat autoimmune diseases, but also to trigger a strong immune response to cancer cells or to life-threatening infections."
Essentially, dendritic cells continuously sample their environment by capturing and swallowing dead or dying cells (either self or non-self) as well as pathogens and displaying fragments of the cells on their surfaces to be recognized by many types of T cells, including killer T cells, helper T cells or Tregs. When EPO interacts with its EPO receptors on the dendritic cells, it causes the dendritic cells to embark on a series of maturation steps that cause them to promote tolerance and selectively activate Tregs that tamp down any immune response to that antigen.
"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," Engleman said.
Conversely, removing the EPO receptor from dendritic cells resulted in tumor regression in mice with immune-resistant melanoma or colon cancer tumors.
"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."
Researchers from University of Tübingen, Germany; Duke University; the University of California, San Francisco; Centre International de Recherche en Infectiologie; ImmunEdge Inc.; the New York Blood Center; Leiden University Medical Center; St. Jude Children's Research Hospital; University of Cincinnati College of Medicine; and the Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, contributed to the work.
The study was funded by the National Institutes of Health (grant numbers CA244114, U54 CA274511, CA251174 and P01 HL149626).
Stanford resources
https://med.stanford.edu/news/all-news/2025/04/epo-tumors.html
