Before He Won the Nobel, We Were Already Listening to the Future

The 2025 Nobel Prize in Physiology or Medicine went to the Japanese immunologist Professor Shimon Sakaguchi.

Two years ago, he taught a class for us at Gaoshan Academy. After that class, I came to understand "the true wisdom of immunity" in a whole new way.

This piece is both a set of study notes and a thank-you to Gaoshan Academy.

How Immunity Works

Many people know that immunity is about "fighting off foreign invaders," but few realise that immunity also has to learn how to "hit the brakes."

Professor Sakaguchi discovered and named regulatory T cells (Treg), showing that they can suppress excessive immune responses and maintain self-tolerance. This line of research went on to become one of the three major themes in immunology, and it is closely tied to many diseases.

Milestones

1995: CD25 is pinned down as a surface marker of Treg;

2000: "Regulatory T cells" are formally named in Cell;

2003: The master control gene Foxp3 is discovered; Foxp3 mutations cause the fatal IPEX syndrome, pointing to Treg as the hub of immune homeostasis.

Professor Sakaguchi often stresses that the goal of the immune system is not to be "permanently fired up," but to reach a kind of "powerful balance" — able to respond to challenges without harming itself. Its applications span allergies, autoimmunity, organ transplantation, cancer and more.

From the perspective of the history of science, this is a paradigm shift: immunology is not just the science of attack, but the science of regulation.

1. Why immunity must "throw punches and also hit the brakes"

Memory and specificity: vaccines work because the first exposure builds antigen-specific memory; when the same antigen shows up again, the secondary response is faster and stronger.

The two-axis dilemma (in plain terms):

Overreaction × self → autoimmunity / allergy

Underreaction × non-self → infection / tumours

The solution is to let Treg act like "police," keeping the "hot-headed effector T cells (Teff)" in check.

2. The "chain of evidence" for Treg

Removing CD25⁺CD4 T cells (the classic Treg population) in mice leads to multi-organ autoimmunity; putting them back eases the inflammation — animal evidence that "the brake exists and works."

IPEX syndrome and Foxp3: infants suffer a body-wide immune "overshoot" and rarely survive; once the cause was identified as a Foxp3 mutation, the Treg–disease–gene chain was complete.

3. Why are "autoimmune diseases" more common in modern society?

The hygiene/affluence correlation": infectious diseases are declining while autoimmune diseases are rising; regions with higher GNP and "cleaner" environments have higher incidence — less stimulation, less training, and a system more prone to imbalance.

4. Attack and defence in cancer immunology: when to "ease off the brake"

Treg are often more abundant in the tumour microenvironment, where they suppress Teff; so approaches such as Anti-CTLA-4, Anti-GITR and Anti-CCR4 are used to "cut back Treg and boost Teff."

The class was also candid: overall efficacy is still limited, "working in about 30% of cases," but within a 20-year horizon, combination strategies and new technologies could significantly widen the range of treatable conditions.

TCR-T vs. CAR-T: CAR-T is mature for blood cancers but limited in solid tumours; TCR-T holds more promise for solid tumours (more precise targeting).

5. Organ transplantation: from "heavy immune suppression" to "engineered tolerance"

Traditional systemic immunosuppression brings risks such as infection and tumours; the class laid out four more precise paths:

Suppress only Teff;

Expand Treg outside the body and infuse them back (already being explored for type 1 diabetes in children);

Use drugs to turn Teff → Treg;

Take Teff out of the body, convert them into Treg, then infuse them back.

Mouse models show that Treg infusion can improve transplant tolerance, with FOXP3 markers rising in the tissue. This is an engineered path that "protects both the organ and the immune system."

6. Translation and entrepreneurship: from "generic Treg" to "specific Treg"

The key tension in bringing this to the clinic: functional stability versus accessible delivery. The class introduced RegCell's approach: take lymphocytes from a patient's blood, culture "antigen-specific Treg" in a targeted way, cryopreserve them, and move toward human trials; the long-term goal is to scale up batches and bring down costs.

7. Q&A

Is it possible to clear only "the Treg inside tumours"? — By finding tumour-specific molecules/receptors; clinical attempts are under way.

NK cell therapy: logical as a first line of defence, but its durability and real-world benefit still need stronger evidence.

Allergies and COVID-19: lots of papers, but no consistent conclusion yet; reasoning from the mechanism, moderately boosting Treg might ease an immune "overshoot."

Take Away

Understanding immunity: stronger is not better — what matters is knowing how to fight and how to stop;

The space to watch: making Treg specific, localised and part of combination therapies will be one of the main threads of the next decade (tumours / autoimmunity / transplantation / pregnancy, etc.);

For industry, two things decide success: differentiated targets + accessibility (convenient delivery, controllable costs, the ability to organise trials);

On a personal level:

Moderate eating, regular exercise, good sleep and stress management, a healthy gut microbiome = "everyday immune engineering."

"Too much is as bad as too little" — balance wins!

Thank You, Gaoshan Academy

Before he won the prize...

they had already brought this future Nobel laureate into our classroom. That day, he spoke about "the balance of immunity," and about "when holding back is actually the smarter move." In that moment I thought: what Gaoshan truly values are new directions that are "not yet widely proven, but coherent and profound."

That takes "academic intuition and patience."

Getting to learn from the professor in the same room before he won the prize was an honour, and also a reminder: true vision means seeing the value of something while it is "still unproven."

Thank you, Gaoshan, for bringing "the future" into our classroom ahead of time;

and thank you to the scientists willing to walk in silence.

May we always keep, between knowledge and common sense, an "unpaved little path" for ourselves.