Your Immune System Has an 'Off Switch'—Scientists Just Found How to Flip It

Scientists have identified the master switch that determines whether your immune system launches an attack or holds back, potentially revolutionizing treatments for everything from cancer to lupus. The discovery centers on erythropoietin (EPO), a molecule best known for making red blood cells, but which also acts as a critical immune system controller.

How Does This Immune Switch Actually Work?

The immune system relies on specialized cells called regulatory T cells, or Tregs, to prevent inappropriate attacks on healthy tissue—a process called peripheral immune tolerance. These cellular peacekeepers were identified in the late 1990s and recently earned researchers the 2025 Nobel Prize in physiology or medicine. However, scientists didn't understand what triggered these protective cells until now.

"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, a professor of pathology at Stanford Medicine. "Now we know the erythropoietin, or EPO, signaling pathway in a subset of dendritic cells called type 1 conventional dendritic cells is what triggers them."

What Makes This Discovery So Significant?

The research reveals that EPO acts as a dual-purpose switch in immune cells called type 1 conventional dendritic cells (cDC1s). These cells constantly patrol the body, capturing dead or dying cells and displaying fragments to other immune cells. When EPO binds to its receptors on these dendritic cells, it triggers a series of changes that promote immune tolerance and activate the protective Tregs.

The Stanford team demonstrated this mechanism using mice that underwent total lymphoid irradiation—a treatment that kills off many immune cells while leaving dendritic cells intact. After this treatment, the mice showed dramatically increased levels of EPO receptors on their dendritic cells, allowing them to permanently tolerate genetically mismatched transplanted organs.

Could This Lead to New Treatments?

The implications extend far beyond transplant medicine. When researchers genetically removed the EPO receptors from dendritic cells, something remarkable happened—the cells transformed from immune suppressors into "super stimulators" that powerfully activated immune responses. This dual nature offers two therapeutic opportunities:

• Autoimmune Disease Treatment: Enhancing EPO signaling could strengthen immune tolerance, potentially treating conditions like rheumatoid arthritis, multiple sclerosis, and lupus by preventing the immune system from attacking healthy tissue
• Cancer Immunotherapy: Blocking EPO receptors could remove the brakes from the immune system, allowing it to mount stronger attacks against cancer cells that typically evade immune destruction
• Transplant Medicine: Fine-tuning this pathway could improve organ transplant success rates by promoting long-term tolerance without broad immune suppression

In cancer experiments, removing EPO receptors from dendritic cells resulted in tumor regression in mice with immune-resistant melanoma and colon cancer.

Meanwhile, researchers at Université Laval are developing a complementary approach using synthetic antibodies to treat autoimmune diseases. Their team created modified antibodies that can bind to the same targets as disease-causing autoantibodies but without triggering harmful immune responses. In mice with MOGAD, an autoimmune disease similar to multiple sclerosis, these synthetic antibodies reduced symptom severity and helped restore mobility.

"This proof-of-concept opens the way to a new range of treatments for autoimmune diseases," said Luc Vallières, the study leader and professor at Université Laval. The approach could potentially be adapted for other human autoimmune diseases involving autoantibodies.

Both discoveries highlight how scientists are uncovering the fundamental mechanisms that control immune system behavior. "It's fascinating that this fundamental mechanism took so long to discover," Engleman noted. "It's even possible that this is the primary function of EPO and that its effect on red blood cell formation is secondary."