The 2025 Nobel Prize in Physiology or Medicine was awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their groundbreaking discoveries on how the immune system maintains peripheral immune tolerance through a specialized population of cells known as regulatory T cells (Tregs).
This recognition honors one of the most elegant stories in modern immunology: the discovery of a cellular and molecular mechanism that prevents the immune system from turning on itself. Yet, as with many great scientific advances, this was not the work of a single moment. It was a journey that unfolded over years, across multiple disciplines and discoveries.
The discovery of active immune tolerance
In 1995, Shimon Sakaguchi and colleagues published a landmark study showing that a small subset of CD4⁺ T cells expressing the IL-2 receptor α-chain (CD25) acted as a brake on immune activation.1 Removing these cells from mice led to the development of multi-organ autoimmune disease, revealing that self-tolerance is not passive; it requires active, cell-mediated suppression. This was the first formal identification of what is now known as regulatory T cells (Tregs).
Subsequent research demonstrated that these cells were anergic in vitro, produced minimal IL-2, and could suppress effector T cells through mechanisms involving CTLA-4, IL-10, and TGF-β. Together, these insights redefine immune regulation as a dynamic balance between activation and suppression, rather than a simple on/off switch.
The molecular key: FOXP3
The story deepened in 2001 when Mary Brunkow and Fred Ramsdell discovered that the fatal lymphoproliferative disorder in the scurfy mouse was caused by mutations in a previously unknown gene on the X chromosome, later identified as Foxp3.2 Around the same time, patients with the severe autoimmune syndrome IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) were found to have mutations in the same gene.
This pivotal finding established FOXP3 as the master regulator of immune tolerance. Work from Sakaguchi, Rudensky, and others has confirmed that Foxp3 expression is both necessary and sufficient for Treg development and function, thereby unifying the cellular and molecular foundations of immune tolerance.3
A new view of immune homeostasis
These discoveries reframed our understanding of immune balance: tolerance is actively maintained, not merely the absence of activation. When this equilibrium is disturbed — by genetic mutation, inflammation, or drug-induced perturbation — the result can be unchecked immunity, autoimmunity, or immune exhaustion.
Understanding the distinctions between these states remains one of the most important frontiers in immunology.
Coming full circle for us at InSphero
At InSphero, this year’s Nobel Prize resonates deeply with our own scientific philosophy: the immune system is not a passive bystander. It is woven into nearly every physiological and pharmacological process.
Our mission to develop immune-competent 3D in vitro models for disease and safety testing stems from this very principle. By embedding immune context through macrophage co-cultures, cytokine feedback loops, or engineered immune interactions, we aim to capture the regulatory dynamics that determine real-world biological responses to therapy.
We focus on integrating immune mechanisms across several domains:
- Disease modeling: where immune–epithelial and immune–stromal crosstalk drives inflammation, repair, and fibrosis.
- Oncology: where the balance between effector and regulatory immune activity dictates tumor evasion or therapeutic success.
- Safety pharmacology: where immune dysregulation underlies drug-induced liver injury, cytokine release, and idiosyncratic adverse reactions processes that cannot be recapitulated in parenchymal-only systems.
By incorporating immune components into our 3D InSight™ platforms, we move closer to modeling the full immune cycle, including tolerance, activation, and resolution, that defines true human physiology.
Immune Tolerance: What the Nobel Prize Recognized
The Nobel Committee’s recognition this year is not only a celebration of past discovery. It’s a reminder that the next breakthroughs in how we model human biology will come from embracing interconnected systems rather than studying them in isolation.
At InSphero, this is exactly what drives us: building models that don’t just mimic organs, but capture the regulatory balance that makes human biology work.
References:
- Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25)” (J. Immunol. 155:1151–1164)
- Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse” (Nat. Genet. 27:68–73)
- Control of regulatory T cell development by the transcription factor Foxp3” (Science 299:1057–1061)
