Ahmad Gamal Saad-Eddin

This piece was originally published in Nature Middle East.

The easy, somewhat simplistic choice in describing the immune system, with all the complexity of its biological processes, is that it is: an “army” or a “line of defense.” This metaphor has gained complete dominance over time in biological science literature. It has become an easy synonym; the immune system protects and mobilizes its troops to defend the body, so it must be an army.

This image has many shortcomings and directs the imagination to create a reductionist world that hides other aspects of this amazing system and its extremely precise molecular processes.

In their article “Understanding Immunity,” published in 2023, researchers Martin Zach and Gregor Greslehner proposed a counter-idea, not entirely new, that using military and defense metaphors in our discussion of immunity causes us to overlook, as metaphors typically do, other extremely important processes in which the immune system plays a primary role.

This year’s Nobel Prize (2025) in Physiology or Medicine goes to this less commonly explored aspect when discussing the immune system. A question that seems simple at first glance, but carries incredible complexity: What makes the immune system target microbes rather than the body itself? The answer to this included the discovery of a type of immune cell that prevents the body from attacking itself.

This discovery has helped develop a large number of autoimmune disease treatments, now undergoing early clinical trials, and is expected to play a major role in treating diseases that affect millions of people’s lives, such as diabetes and rheumatological diseases.

Their Name is T Cells

The “T” here is short for “Thymus,” located in the upper part of the chest, in the anterior mediastinum, directly in front of the heart muscle. It is large in children and atrophies during adolescence and puberty. What concerns us about it is that it is the organ in which immune cells mature and become effective.

T cells, which are white blood cells not yet “T” cells, originate in the bone marrow, then migrate to the thymic gland to undergo an extremely important phase of their development, where they learn how to distinguish between healthy and damaged cells, and between what constitutes the body’s cells and what is not, such as viruses and bacteria. They then exit into the bloodstream, having grown and matured into T cells, to join what we know as the immune system, immune cells that recognize the body’s cells and do not attack them.

In 1995, Shimon Sakaguchi, a Japanese scientist, discovered a previously unknown subtype of T cells, which he called regulatory T cells. These cells play a pivotal role—special brakes, another metaphor, for the immune system, preventing it from acting wildly. These regulatory cells represent only 2% of the total T cells in the body, but they have complete control. Sakaguchi discovered that this biological pathway, which prevents the body from attacking itself, means that among T cells, there are specific T cells specialized in regulating the work of T cells.

At that moment in history, the consensus among immunologists was that the immune system has a self-regulatory mechanism. But no one knew exactly how the system could do this, and consequently, autoimmune diseases were an incomprehensible mystery.

In a series of experiments famous among immunologists, Sakaguchi revealed that mice lacking these cells typically develop a range of autoimmune diseases, in which the body attacks itself, specifically its internal organs such as the thyroid and pancreas. And that injecting these animals with these regulatory T cells clearly stopped their deterioration and disease progression.

It took six years for Mary Brunkow and Fred Ramsdell, both American, to pick up this thread, this time at the genetic level. The two scientists discovered that there is a genetic mutation, specifically in the FOXp3 gene, that causes a severely dangerous immune disorder in mice, and that this gene has a counterpart in humans. This discovery was not easy. The truth is that the change causing this mutation is extremely subtle, to the point of being difficult to distinguish, even though its effect is very clear at the same time.

What’s amusing here is that Sakaguchi came back to pick up the thread again in 2003, conducting a series of experiments on this specific gene, discovering that the hypothesis was correct, that this gene specifically appears in regulatory T cells, and that it is an essential element in their function.

Reviving an Old Hypothesis

In the mid-1970s, the hypothesis we now know to be correct about a special type of regulatory T cells was proposed for the first time. Scientists found no trace of them, but they realized their existence. They called them at the time: “suppressor T cells.” Perhaps, they told themselves, there is some reason for autoimmune diseases to occur. The body must be attacking itself, because these diseases don’t come from outside. They’re not a virus, bacteria, or parasite of some kind. Not a microorganism we can’t see. The body must be attacking itself for some reason.

Scientists nevertheless failed to find any trace or evidence of these cells. They said: We must be wrong then. Nothing new. Just another incorrect hypothesis. One of the many paths that science, medicine this time, takes to discover that the road leads nowhere, and then everyone turns back searching for another hypothesis.

Sakaguchi didn’t turn back with them. For some reason, he insisted on exploring this area. And at a time when this idea was unexplored in the immunology community, this scientist was conducting a series of precise experiments with his team, attempting to find these cells.

The discoveries of Sakaguchi, Pronko, and Ramsdell, who received this year’s Nobel Prize in Physiology or Medicine, launched a wide wave whose effects continue to this day.

A new field emerged into the light simply because of ideas that weren’t previously proposed at all. And the idea here is also simple and logical. Why don’t we use these cells then to develop new treatments?

More than 200 clinical trials are currently attempting to search for immunotherapies that employ these results to their advantage, specifically regarding the role of some regulatory T cells in dealing with cancerous tumors. One of the interesting things is that this type of cell is usually observed in some cancers, and there is a new hypothesis saying that they may play a role in suppressing the immune response to tumors, which means that targeting these cells in the context of tumors may yield positive results in the long term.

In contrast to that hypothesis, there are other treatments looking at the issue of using some regulatory T cells as a way to stop the body’s violent response after organ transplantation. It may be possible to suppress the immune system in this context and prevent it from targeting foreign bodies, perhaps only if we can employ these cells.

It’s no longer about simple, reductionist metaphors. Science has moved beyond that, or we’re about to move beyond it, and over time, we discover a precise regulatory network in which regulatory T cells play a fundamental role. What was once a forgotten hypothesis that no one paid attention to has become one of the promising horizons in this field. A movement fueled by doubt and the unfamiliar, and sometimes by intuition that has nothing to support it.