The 2025 Nobel Prize in Physiology or Medicine has been awarded to Japanese scientist Shimon Sakaguchi and American scientists Mary E. Brunkow and Frederick J. Ramsdell for their pioneering discoveries on regulatory T cells. These cells act as essential "security guards" in the immune system, ensuring it fights off harmful invaders like viruses and bacteria without mistakenly attacking the body's own healthy cells. This breakthrough, announced by the Nobel Committee, highlights the mechanism of peripheral immune tolerance and opens new pathways for treating autoimmune diseases and enhancing cancer therapies, addressing a long-standing puzzle in immunology.
What Is the Immune System and How Does It Normally Function?
The immune system is like the body's defense force, made up of cells, tissues, and organs that work together to protect against harmful invaders such as bacteria, viruses, and other microbes.
It has two main parts: the innate immune system, which provides quick, general protection, and the adaptive immune system, which learns to target specific threats.
Key players include white blood cells like T cells, which are produced in the bone marrow and mature in the thymus gland. T cells help identify and destroy infected or abnormal cells.
Normally, the immune system is highly precise—it attacks only foreign threats while ignoring the body's own cells to avoid self-harm. This balance is maintained through processes called immune tolerance.
What Is Immune Tolerance and Why Is It Important?
Immune tolerance is the immune system's ability to recognize and not attack the body's own proteins, cells, and tissues, while still responding to dangers. Without it, the body could turn on itself, leading to autoimmune diseases like rheumatoid arthritis or type 1 diabetes.
There are two types: central tolerance, which happens in the thymus where harmful T cells are eliminated early, and peripheral tolerance, which occurs outside the thymus to handle any remaining risks.
Immune tolerance is crucial because the body faces constant threats—thousands of microbes try to invade daily—but attacking healthy cells would cause chronic inflammation and organ damage.
How Was the Concept of Regulatory T Cells Discovered?
In the 1980s, scientists knew about central tolerance but puzzled over why some self-attacking T cells still escaped. Earlier theories suggested special "suppressor" T cells existed to control them, but this idea was dismissed due to lack of evidence.
Shimon Sakaguchi challenged this in experiments with newborn mice. He removed their thymus at three days old, expecting a weak immune system, but the mice developed autoimmune diseases from overactive immunity. Injecting T cells from healthy mice prevented this, suggesting a regulatory subset.
In 1995, Sakaguchi published evidence for these regulatory T cells (Tregs), which suppress other T cells. Despite skepticism, his work revived the field.
What Role Does the FOXP3 Gene Play in This Process?
The FOXP3 gene is a master controller, acting like a switch that turns on the development and function of regulatory T cells. Mary Brunkow and Frederick Ramsdell discovered this in the 1990s while studying "scurfy" mice, which have flaky skin and die young from T cells attacking their bodies.
After mapping mouse DNA, they identified FOXP3 mutations as the cause in 2001. This gene produces a protein that regulates gene expression in Tregs, ensuring they identify and suppress self-attacking immune responses.
In humans, FOXP3 defects cause IPEX syndrome, a rare disorder where the immune system attacks the intestines, skin, and endocrine glands, often fatal in infancy without treatment. By 2003, Sakaguchi used this to confirm FOXP3's essential role in Tregs.
What Are Regulatory T Cells and How Do They Work?
Regulatory T cells, or Tregs, are a small subset of T cells (about 5-10% of all T cells) that act as peacekeepers in the immune system. They patrol the body and suppress excessive or misguided immune responses by releasing signaling molecules or directly interacting with other immune cells. For example, Tregs can block killer T cells from attacking healthy tissues. They express the FOXP3 protein, which helps them recognize self-proteins.
In healthy people, Tregs maintain balance, but in autoimmune diseases, their numbers or function drop, leading to self-attacks. Conversely, in cancer, tumors recruit extra Tregs to hide from the immune system.
What Are the Implications for Autoimmune Diseases?
Autoimmune diseases occur when the immune system loses tolerance and attacks the body, affecting over 80 conditions like multiple sclerosis (attacking nerves) or lupus (attacking multiple organs).
The Nobel discoveries explain why: low Treg activity or FOXP3 mutations disrupt peripheral tolerance. Treatments now focus on boosting Tregs—for instance, clinical trials modify patients' Tregs in labs and reinfuse them to restore balance. This could reduce reliance on broad immunosuppressants, which weaken overall immunity and increase infection risks.
In India, where autoimmune diseases affect millions (e.g., 1 in 1,000 for rheumatoid arthritis), these insights could lead to targeted therapies.
How Does This Relate to Cancer Treatment?
In cancer, the immune system often fails to attack tumors because cancer cells mimic healthy ones or attract Tregs to suppress attacks. The discoveries enable immunotherapies that block Treg function, allowing killer T cells to target tumors.
For example, CAR-T cell therapy modifies T cells to fight blood cancers but faces Treg barriers; new drugs reduce Tregs to enhance it. However, this risks autoimmune side effects. As per experts like Dr. Hasmukh Jain from Tata Memorial Hospital, many new therapies work by dialing down Tregs.
Globally, cancer immunotherapy markets are growing, with India investing in affordable CAR-T options since 2023 approvals.
What Is the Background of Central vs. Peripheral Tolerance?
Central tolerance is the first checkpoint: in the thymus, T cells that strongly bind to self-proteins are destroyed or reprogrammed—about 95% are eliminated. But some slip through, so peripheral tolerance provides backup.
Tregs handle this by actively suppressing responses in tissues like the gut or skin. Without peripheral tolerance, even minor infections could trigger widespread self-attacks. Historical studies in the 1960s showed thymus removal causes autoimmunity, but the Nobel work pinpointed Tregs as the mechanism.
What Are the Broader Applications for Organ Transplants?
Organ transplants are rejected because the immune system sees donor tissues as foreign. Tregs could prevent this by promoting tolerance. Trials are testing Treg infusions to reduce anti-rejection drugs, which have side effects like infections.
In India, with over 200,000 annual transplant needs but only 15,000 performed, this could improve success rates (currently 90% for kidneys but lower long-term). The discoveries also aid understanding IPEX and scurfy models for drug testing.
What Challenges and Future Directions Exist?
Challenges include precisely targeting Tregs without causing imbalance—too few lead to autoimmunity, too many to unchecked infections or cancer. Future research focuses on gene editing (like CRISPR) to fix FOXP3 mutations or engineer better Tregs.
Globally, over 100 Treg trials are ongoing. In India, institutions like AIIMS and ICMR are exploring these for local diseases. The Nobel highlights how basic science leads to therapies, emphasizing funding for immunology research.
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