Healthcare (Commonwealth Union) – Stanford Medicine researchers have discovered that a single signaling pathway determines whether immune cells attack or tolerate the cells they encounter while patrolling the body. By influencing this pathway, scientists may be able to control immune responses to treat a variety of conditions, including cancer, autoimmune diseases, and situations requiring organ transplants.
The study, conducted in mice, sheds light on the mechanisms behind a critical immune process that prevents the immune system from mistakenly targeting healthy tissue. This process, known as peripheral immune tolerance, is regulated by specialized cells called regulatory T cells (Tregs), first identified in the late 1990s—a discovery recently honored with the 2025 Nobel Prize in Physiology or Medicine.
Edgar Engleman, MD, professor of pathology indicated that the Nobel Prize recognized the discovery of regulatory T cells and their role in immune tolerance, but at that time, they did not know what activated them.
He further pointed out that their work shows that the erythropoietin (EPO) signaling pathway in a subset of dendritic cells, called type 1 conventional dendritic cells, is responsible for triggering Tregs and he is very excited because manipulating this pathway could eventually provide therapies for a wide range of diseases.
Engleman, a member of the Stanford Cancer Institute, is the senior author of the study published on Dec. 10 in Nature. Xiangyue Zhang, PhD, senior research scientist, served as the lead author.
The vital process of developing immune tolerance to the body’s own cells occurs in two main stages. The first, known as central immune tolerance, takes place in the bone marrow and thymus. Here, B cells and T cells go through an initial screening that either eliminates or reprograms those that react against the body’s own tissues before they enter the bloodstream. The second stage, peripheral immune tolerance, acts as a safeguard, checking circulating immune cells that might have slipped past the first screening.
The consequences are significant. When the immune system becomes overly active and mistakenly targets healthy tissues, autoimmune disorders like rheumatoid arthritis, multiple sclerosis, lupus, and diabetes can develop. Conversely, if the immune response is insufficiently robust, cancer cells may escape detection and elimination, thereby proliferating unchecked.
This equilibrium between immune attack and tolerance is maintained by regulatory T cells (Tregs), which function to suppress the inappropriate activation of other immune cells, including T and B cells, thereby preventing potentially damaging attacks on the body’s own tissues.
“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,” explained Engleman. “We not only discovered this mechanism, but we also learned how it can be turned on and off.”
The scientists employed an experimental technique first tested in mice and later in humans, where exposing the thymus, spleen, and lymph nodes—key hubs for immune cells—to radiation eliminates a large portion of T cells and B cells while largely sparing antigen-presenting cells like dendritic cells. This procedure, known as total lymphoid irradiation, effectively reprograms the patient’s immune system to permanently accept transplanted cells or organs that are genetically different.
This strategy presents a dual utility, potentially serving to either promote immune tolerance in the context of autoimmune diseases or, conversely, to activate a vigorous immune response against malignant cells or pathogenic infections.
Nevertheless, dendritic cells function within a network; they recruit other immune cell types, most notably T cells, to carry out their activities.
Engleman elucidated that all T cells, encompassing regulatory T cells (Tregs), necessitate initial exposure to an antigenic structure, recognised by their receptors, to undergo maturation into cells capable of either targeting threats or dampening immune responses.He further indicated that Dr. Zhang and him hypothesized that the initiation of either tolerance or activation relies on antigen-presenting cells.
Type 1 conventional dendritic cells, known as cDC1s, are particularly adept at engulfing dying cells or pathogens and presenting fragments of them like immunological bait, effectively signaling T cells to respond.
