Decoding the Nobel winner: Peripheral immune tolerance

The discovery of Tregs has opened a thrilling new frontier in therapeutics, writes Arun Panchapakesan.

We now know that T cells, a critical component of the immune system, mature in the thymus. It is here that they learn a crucial lesson: the thymus acts as a quality control centre, allowing T cells that recognise foreign pathogens to survive while eliminating those that would attack the body’s own tissues. This process of weeding out self-reactive T cells is termed ‘central tolerance’.

While studying this process in the late 1960s and 1970s, scientists observed something peculiar: Removing the thymus in newborn mice not only weakened their ability to fight infections but, paradoxically, often led to autoimmune diseases, in which the body’s own T cells attack its tissues.

The timing of the removal, however, produced a dramatic difference. Removing the thymus on day 3 after birth led to severe autoimmunity, whereas removal on day 7 largely protected the mice from it. This paradox suggested that something crucial must happen in the thymus between days 3 and 7 to prevent T cells from attacking the body’s own tissues. The question was: what?

Although unknown at the time, we now know the thymus is not foolproof. Some self-reactive T cells inevitably escape into the bloodstream. Yet, they usually do not cause harm. The reason is a second line of defence known as peripheral tolerance—the very process those newborn mice were developing between days 3 and 7. The discovery of this process and the cells responsible for it earned Shimon Sakaguchi, Mary Brunkow, and Fred Ramsdell the Nobel Prize in Physiology or Medicine this year.

At the heart of peripheral tolerance is a specialised class of T cells, regulatory T cells (Tregs), which are also generated in the thymus. Tregs actively suppress immune responses directed against the body’s own tissues. In mice, their development begins after day 3, explaining why removing the thymus on day 7 was not catastrophic: by then, enough Tregs had formed to keep the escaped self-reactive T cells in check.

Tregs achieve this through several specialised mechanisms. Normally, when a T cell recognises its target, it rapidly divides and releases chemical signals to recruit other immune cells, such as B cells and macrophages. Tregs intervene to prevent this. For instance, they display a surface protein called CD25, which acts like a sponge, soaking up an essential growth signal (IL-2) that other T cells need to multiply. By capturing this signal, Tregs starve nearby T cells of the stimulus required for proliferation. Furthermore, Tregs release calming molecules like IL-10 and TGF-β, which directly suppress the activation of other immune cells and help restore balance once a threat has passed.

The CD25 molecule was key to Shimon Sakaguchi’s groundbreaking identification of Tregs in 1995. At Kyoto University, he showed that removing CD25-carrying T cells from healthy mice caused them to develop autoimmune diseases rapidly. When these same cells were reintroduced, the disease was suppressed, conclusively demonstrating that Tregs are essential for immune control.

This discovery raised a new question: how are Treg cells formed in the first place?

The answer emerged from the work of Mary Brunkow and Fred Ramsdell. They were studying a mysterious inherited disease in mice that caused severe immune activation and early death. Their research pinpointed a gene called FOXP3, which produces a protein that acts as a master regulator of immune balance. Mutations in this gene caused a complete loss of immune control, resulting in rampant autoimmunity. Similar mutations were later found in children with IPEX syndrome, a rare and severe autoimmune disorder, confirming the gene’s crucial role in humans.

Sakaguchi later showed that the FOXP3 protein acts as the master switch for Treg development and function, linking his earlier discovery of CD25⁺ T cells to the genetic mechanism that gives them their suppressive power.

Today, we know Tregs do much more than maintain peripheral tolerance. They help control inflammation, prevent excessive tissue damage during infections, support wound healing, and influence metabolism. Consequently, Treg dysregulation is implicated in a range of diseases, from autoimmune conditions like type 1 diabetes and multiple sclerosis to cancers and chronic infections where the immune response is insufficient.

The discovery of Tregs has not only rewritten textbooks but also opened a thrilling new frontier in therapeutics. Scientists are now actively developing ways to harness the power of these cells. In one approach, they are creating therapies that boost the number or function of Tregs to treat autoimmune diseases and prevent organ transplant rejection.

In a seemingly opposite but equally promising strategy, they are developing drugs that temporarily inhibit Treg function within tumours, “releasing the brakes” on the immune system to help the body’s own T cells attack cancer. This dual potential—to either suppress or unleash immunity on demand—highlights Tregs as a master control switch for human health.

These insights underscore the monumental importance of the Treg discovery. This year’s Nobel Prize, therefore, recognises the identification of a fundamental principle of the immune system, and perhaps of life itself: that restraint is as valuable as aggression.

(The writer is an assistant professor of molecular biology at a Chennai-based research centre)