2025 Nobel Laureate SAKAGUCHI Shimon: The Boundary Between Self and Non-Self - Science View

The Discovery of Regulatory T Cells and Immune Tolerance: A Detailed Summary

Key Concepts:

• Regulatory T Cells (Tregs): A subset of T cells crucial for suppressing immune responses and maintaining immune tolerance.
• Immune Tolerance: The ability of the immune system to not react against the body’s own tissues (self) and harmless foreign substances.
• CD5: A surface antigen on T cells, initially investigated for its role in distinguishing between self and non-self.
• CD25: A surface antigen identified as a marker for regulatory T cells.
• FoxP3: A key transcription factor essential for the development and function of Tregs.
• Autoimmune Diseases: Conditions where the immune system attacks the body’s own tissues (e.g., rheumatoid arthritis, type 1 diabetes).
• Peyer’s Patches: Areas in the small intestine where the immune system learns to tolerate beneficial gut bacteria.
• Self vs. Non-Self Discrimination: The fundamental ability of the immune system to distinguish between the body’s own cells and foreign invaders.

I. The Initial Quest: Distinguishing Self from Non-Self

Dr. Tasuku Honjo’s research, beginning in 1976 after graduating from the Faculty of Medicine, centered on understanding the fundamental principle of the immune system: the ability to differentiate between “self” (the body’s own tissues) and “non-self” (foreign invaders like viruses and bacteria). He noted the inherent challenge in immunology – the immune system must be strong enough to fight off threats, but not so strong as to attack the body itself. He initially focused on identifying markers on T cells that could distinguish between these two states, believing a key to understanding autoimmune diseases lay in this distinction. He described this initial problem definition as “quite attractive.”

The immune system concentrates approximately 70% of its cells in areas like the gut, ready to combat pathogens entering the body. When these cells identify a pathogen, they release signaling molecules to activate the immune response. However, a dysregulated immune system can mistakenly attack the body’s own tissues, leading to autoimmune diseases like rheumatoid arthritis and type 1 diabetes. Dr. Honjo emphasized that a crucial control mechanism must exist to prevent this from happening.

II. The CD5 Investigation and Initial Obstacles (1976-1983)

Dr. Honjo began by examining T cells expressing the CD5 marker. He hypothesized that CD5-positive T cells might play a role in suppressing excessive immune responses. He conducted experiments using mice lacking a thymus (essential for T cell development) and transferring T cells with varying levels of CD5 into these mice. Mice receiving T cells with almost no CD5 developed autoimmune disease, suggesting a suppressive role for CD5-positive cells.

However, a significant obstacle arose: approximately 80% of all T cells examined expressed high levels of CD5. This made it difficult to isolate the specific cells responsible for immune suppression. He stated, “It was difficult to narrow it down further than just identifying CD5-expressing lymphocytes when disease occurred.” This led him to seek advanced technologies and expertise in the United States in 1983.

III. The Discovery of CD25 and Regulatory T Cells (1983-1995)

In the US, advancements in technology allowed for more detailed analysis of T cell surface markers. Through meticulous experimentation, involving repeated injections and observation of outcomes, Dr. Honjo identified CD25 as a marker for a specific subset of T cells with suppressive function. He declared, “This is it. The regulatory T cell.” He felt this discovery represented a breakthrough, stating, “With this, I thought I could explain everything. Even just looking at 10% [of cells] causes significant events. It felt like I had overcome a wall.”

This discovery, made in 1995, revealed that these regulatory T cells (Tregs) release signaling molecules (cytokines) to control cells that could trigger autoimmune diseases.

IV. The Role of FoxP3 and Collaborative Research (1995-2001)

While the discovery of Tregs was significant, the underlying mechanism remained unclear. Dr. Honjo acknowledged that the research wasn’t conducted in isolation. He participated in small, informal meetings with researchers worldwide who were independently exploring similar ideas. He emphasized that the field wasn’t “isolated” but rather a collaborative effort.

A pivotal moment came with the work of Dr. Mary Brun and Dr. Rams, who identified the FoxP3 gene as crucial for Treg development and function. Their 2001 publication in Nature Genetics demonstrated that a mutation in FoxP3 caused a specific autoimmune disease. Dr. Honjo’s team quickly recognized the connection. He explained, “FoxP3 is a transcription factor, and just like Tregs, a lack of FoxP3 causes autoimmune reactions. This suggests that FoxP3 is a key master regulator for Tregs.”

They confirmed this by introducing FoxP3 into T cells that were not Tregs, resulting in those cells acquiring immune-suppressing capabilities. This solidified the link between FoxP3 and Treg function.

V. Validation and Recognition (2001-2025)

Dr. Honjo’s team, particularly researcher Shōhei Mori, was among the first to publish their findings linking FoxP3 to Treg function. He credited Mori’s dedication and the team’s hard work for their success. The publication was well-received within the immunology community, largely due to Dr. Honjo’s established reputation and the clarity of their findings. He noted that his prior standing in the field likely contributed to the paper’s positive evaluation.

The discovery of Tregs and their reliance on FoxP3 has broad implications, extending beyond autoimmune diseases to areas like cancer immunotherapy. Clinical trials are underway at Japan’s National Cancer Center to explore how Tregs can be manipulated to enhance cancer treatment. The presence of numerous Tregs within tumors can suppress the immune response against cancer cells, and strategies to target these Tregs are being investigated.

VI. Immune Tolerance and the Future of Immunology

Dr. Honjo drew an analogy between the cellular world and human society, suggesting that both require control mechanisms to maintain order. Just as society regulates harmful individuals, the immune system regulates potentially destructive immune cells. He emphasized that understanding fundamental principles is key to unlocking broader applications.

He concluded by stating that the boundary between self and non-self is a lifelong challenge for the immune system. He believes that further research into the mechanisms of regulatory T cells will lead to new approaches in medical treatment, highlighting the importance of collaborative research and the pursuit of fundamental scientific understanding. He noted that while funding can accelerate progress, the most important thing is to pursue what one finds interesting and meaningful.

The 2025 Nobel Prize in Physiology or Medicine was awarded to Dr. Honjo for his groundbreaking discoveries concerning peripheral immune tolerance, a critical mechanism preventing the immune system from harming the body. This work has fundamentally changed our understanding of the immune system and opened new avenues for treating a wide range of diseases.