Stanford Researchers Discover the Immune System’s Master "On-Off" Switch
- Dec 11
- 2 min read
For more than a century, immunologists pondered the "dread of self-poisoning," or horror autotoxicus, a term coined by Paul Ehrlich to describe the paradox of a potent immune system that defends against pathogens without attacking its own tissues. This necessary self-tolerance, or immunological self-tolerance, is a foundational principle of immunology. The mechanism behind this balance was revealed through the discovery of Regulatory T cells (Tregs), specialized immune cells that actively control the immune system and prevent harmful inflammation against self-tissues, commensal microbes, and even a developing fetus.
The scientific road to accepting Tregs was challenging, with the concept of "suppressor T cells" largely abandoned after the mid-1980s. However, the field swung back in 1995 when Shimon Sakaguchi successfully identified and termed them regulatory T cells, demonstrating that depleting a small CD25-positive T-cell population led to uncontrolled autoimmunity in mice. The central importance of Tregs and peripheral immune tolerance was recently affirmed when Shimon Sakaguchi, Fred Ramsdell, and Mary Brunkow were awarded the Nobel Prize in Physiology or Medicine in 2025 for their work. Further confirming their vital role, mutations in the FOXP3 gene, the master regulator for turning a T cell into a regulatory T cell, cause a life-threatening X-linked immune deficiency syndrome (IPEX) in humans, providing tragic proof that this switch is essential for self-tolerance.
While the 2025 Nobel Prize recognized the discovery of Tregs, the exact molecular mechanism that triggers their activation remained unknown. New findings from researchers at Stanford Medicine have illuminated this process, identifying a single signaling pathway that acts as the immune system's 'on-off' switch.
This mechanism involves erythropoietin (EPO), a protein traditionally known for driving red blood cell production. Scientists found that EPO, acting through its receptor (EPOR) on specialized immune cells called dendritic cells (DCs), triggers these DCs to become "tolerogenic," which, in turn, drives the differentiation of naive T cells into Tregs. When the EPO receptor was deleted in mouse models, the dendritic cells converted into "super stimulators," powerfully activating an immune response, leading to the rejection of transplanted tissue.
The discovery that the EPO signaling pathway dictates whether the immune system attacks or befriends an antigen provides a "dual opportunity" for clinical manipulation. By manipulating this pathway, researchers hope to toggle the immune response to treat a wide range of diseases.
For autoimmune disorders and organ transplantation, inducing tolerance via the EPO pathway could suppress harmful immune responses. Conversely, blocking the EPO receptor on dendritic cells converts them into powerful immune activators. This approach has shown promise in mice with melanoma and colon cancer tumors, where removing the EPOR resulted in tumor regression by decreasing Tregs and increasing anti-tumor T cell responses. The continuous effort to precisely define the biology of Tregs and this newfound pathway is the ultimate path toward turning Nobel-winning discoveries into life-saving therapies.
🔖 Sources
Keywords: Immune System’s Master "On-Off" Switch
Immune System’s Master "On-Off" Switch
Four years ago, my husband was diagnosed with IPF (Idiopathic Pulmonary Fibrosis), a moment that changed our lives significantly. For more than two years, he followed his prescribed medications and attended regular medical checkups. Despite this, his symptoms persisted, and we remained concerned about his overall health. He struggled with low energy, frequent discomfort, and the emotional stress that came with ongoing uncertainty.In search of additional support, we decided last year to explore a herbal treatment program offered by NaturePath Herbal Clinic. We approached it cautiously and without high expectations. Over time, however, we began to notice encouraging changes. His tiredness eased, his digestion became more stable, and he appeared stronger and more at ease overall. Little by little, his…