The Power of Tregs: From Sakaguchi’s Nobel Discovery to EpiVax Innovation
If you know us, you know we love Tregs. Regulatory T cells (Tregs) are central to how we think about the immune system and nearly everything we do at EpiVax. So, we were thrilled to see this year’s Nobel Prize in Physiology or Medicine awarded in part to Distinguished Professor Shimon Sakaguchi, MD, PhD, for his discovery of peripheral immune tolerance.
The Discovery That Defined Immune Tolerance
In his landmark 1995 paper, Sakaguchi demonstrated that a subset of CD4⁺ T cells expressing CD25 could suppress autoimmune responses in mice. This finding identified a previously unrecognized population of regulatory T cells capable of maintaining self-tolerance, a concept that initially faced skepticism.
His work laid the foundation for understanding how the immune system distinguishes “self” from “non-self” and revealed that immune suppression is not passive—it’s an active, regulated process.
Thanks to Sakaguchi, Tregs are now recognized as key players in maintaining immune homeostasis and preventing autoimmunity, with broad implications across transplantation, infectious disease, and cancer immunotherapy.
(Did you hear about the Tregs as Medicine: Tolerance and InTolerance Symposium we just held in Tokyo? More on that later.)
From Discovery to Application: EpiVax and the Treg Connection
Sakaguchi’s discovery changed how we think about immune regulation—and it sparked decades of curiosity and innovation at EpiVax.
In 2008, we discovered Tregitopes, short peptide sequences within human IgG that naturally activate regulatory T cells and help the immune system maintain immune tolerance.
Tregitopes bind multiple MHC class II molecules, suppress effector T-cell responses, and upregulate Treg-associated cytokines and chemokines across various disease models. They offer a natural way to modulate immune responses, providing a safer alternative to conventional immunosuppressive drugs.
JanusMatrix: Predicting Tolerance Through Sequence Similarity
Recognizing the broader implications of Tregitopes led us to ask a bigger question: could we systematically identify other epitopes likely to be tolerated by the human immune system?
That question led to JanusMatrix, our in silico algorithm for assessing the tolerogenic potential of T-cell epitopes. JanusMatrix analyzes TCR-facing residues of candidate epitopes for cross-conservation with the human proteome. Sequences that resemble self are more likely to be tolerated or stimulate Tregs, while those that appear foreign tend to provoke effector immune responses.
This epitope-level characterization is essential for accurate immunogenicity risk assessment. It allows us to distinguish sequences likely to induce tolerance from those that might trigger unwanted immune responses—and provides a mechanistic framework for understanding immune regulation in both vaccines and biologics.
By combining insights from Tregitopes and JanusMatrix, EpiVax has built a robust approach to predicting and guiding immune responses, long before others in the field were asking these questions.
New Research Highlights the Power of Tregs
A recent paper in Science by Peter Savage and colleagues at the University of Chicago highlights the precision with which Tregs enforce tolerance during infection.
The study, Regulatory T cells constrain T cells of shared specificity to enforce tolerance during infection, demonstrates that CD4⁺ Foxp3⁺ regulatory T cells selectively control conventional T cells that share self-specificity, preventing autoimmunity while allowing protective responses against pathogen-derived peptides.
This finding reinforces a principle we’ve long relied on at EpiVax: the immune system can encounter pathogen sequences that resemble self, and these self-like epitopes can be selectively tolerated. Tools like JanusMatrix help us identify those epitopes, providing insight into which sequences are likely to trigger regulatory versus effector responses.
During infection, Tregs act as gatekeepers, restraining autoreactive T cells while leaving pathogen-specific T cells free to respond. Understanding this selective control is essential for designing safer, more effective biologics and vaccines.
EpiVax and the Future of Immune Toleranc
At EpiVax, we’ve been on the Treg bus for a long time—well before the field fully appreciated the power of these cells. Dr. Sakaguchi’s Nobel Prize is a moment to celebrate not just his discovery, but the entire field of immune tolerance that his work launched.
Tregs are now central to research across autoimmunity, transplantation, and cancer therapy, and it’s exciting to see the world catching up to ideas we’ve been exploring for decades.
We were thrilled to bring many of these concepts together at the recent Tregs as Medicine: Tolerance and InTolerance Symposium in Tokyo, where researchers shared how Tregs are being applied to new therapies—30 years after their discovery. We were honored to hear from Dr. Sakaguchi himself, just days before he was awarded the Nobel Prize.
You can explore the full program and abstracts here.
Conclusion: Riding the Treg Bus Into the Future
So, the question remains—are you on or off the Treg bus?
We’ve been riding it for a long time, and the journey is only getting more exciting.
At EpiVax, our computational immunology tools and decades of immunology expertise continue to advance understanding of immune regulation, guiding the design of smarter biologics and vaccines with reduced immunogenicity risk and enhanced safety.
Interested in learning more?
Explore how EpiVax’s in silico immunogenicity assessments and tolerance modeling tools like JanusMatrix and Tregitopes are helping developers design better biologics and vaccines.
Learn more about our Immunogenicity Risk Assessment services.
