Reprogrammed Tregs offer a targeted approach to restoring immune tolerance in autoimmune disease.
Over four decades ago, a surprising observation hinted at a specialized T cell population capable of suppressing autoimmunity. Now known as regulatory T cells, or Tregs, these immune modulators are central to the immune system’s ability to distinguish self from non-self. Scientists responsible for the foundational work on Tregs were recognized with the 2025 Nobel Prize in Physiology or Medicine for discoveries in peripheral immune tolerance.
Shimon Sakaguchi, MD, PhD
Distinguished Professor
Immunology Frontier Research Center
Osaka University
Cofounder, RegCell
In this Innovation Spotlight, immunologist and Nobel Prize winner Shimon Sakaguchi from Osaka University reflects on foundational discoveries, the mechanisms behind Treg function, and the therapeutic promise of Tregs. Sakaguchi’s history of researching these cells has led him to help found RegCell, a biotechnology company at the forefront of developing reprogrammed Treg cell therapies designed to treat autoimmune diseases by restoring immune balance.
What were the first observations that led you to suspect the existence of the cells that ultimately became known as Tregs?
It was first demonstrated in the late 1970s that the inoculation of T cell suspensions could prevent the development of autoimmune disease and inflammatory tissue damage in neonatally thymectomized mice.1 The cells responsible turned out to be CD4+ T cells, which are continuously produced in the thymus.
How do Tregs regulate the immune system, and how are they disrupted in autoimmune diseases?
Tregs suppress immune responses via two mechanisms: humoral factor-dependent and cell contact-dependent. Tregs can secrete the inhibitory cytokine IL-10 to exert an immunosuppressive effect,2 and this is important especially in the control of mucosal immunity. They can also downregulate the expression of CD80/CD86 costimulatory molecules and upregulate coinhibitory molecules such as PD-L1 on antigen-presenting cells, thereby suppressing the activation and expansion of naive and activated T cells. They also function through a cell contact-dependent mechanism, which is critically important for preventing and suppressing autoimmune disease, as genetic anomalies or variations of the molecules involved in this mechanism, such as CTLA-4 that is constitutively expressed by Tregs,3 can be an underlying cause of a variety of autoimmune diseases.
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Why is developing therapies for autoimmune diseases so important?
There is a significant unmet need in treating autoimmune diseases. According to the Global Autoimmune Institute, approximately 10 percent of the global population is estimated to be afflicted with some sort of autoimmune disorder. For many with an autoimmune disease, it is a chronic condition, and only palliative treatments are available, leading to high and sustained costs for healthcare systems.
What inspired you to develop reprogrammed Tregs, and what utility will they have?
Reprogrammed Tregs represent a superior alternative to current therapies for autoimmune disease, such as steroids, cyclosporin A, and tacrolimus, which are largely antigen-nonspecific and can have significant adverse effects from long-term use, such as recurring infections, increased risk of cancer, and potential organ toxicity. What was required, and what reprogrammed Tregs can provide, is disease-specific suppression and ideally re-establishment of stable immune self-tolerance in patients with autoimmune diseases. In this regard, antigen- or disease-specific Treg cells are able to achieve disease-specific suppression in a more physiological manner and for the longer term as a “living drug.”4
What is the process for making reprogrammed Tregs, and what successes have you had so far?
Two technologies are required for the purpose of converting disease-mediating T cells into Tregs. One is a method for achieving high and constitutive expression of the Treg-specific master transcription factor Foxp3.5 The other approach is to drive the induction of Treg-specific epigenetic changes in Treg functional genes. We have developed these two technologies and have shown that disease-mediating T cells can indeed be converted to functionally stable Treg cells in mice and humans.6,7
How does RegCell’s Treg platform compare to current autoimmune disease therapies?
As discussed above, it can achieve antigen- or disease-specific immune suppression by acting as a “living drug,” unlike steroids or other immunosuppressive drugs. RegCell’s Treg platform does not require gene manipulation for preparation, unlike CAR-Tregs. Furthermore, our Tregs can be produced in large quantities and frozen for later reuse for the treatment of chronic or recurrent diseases, unlike natural Tregs.
What challenges do you expect to face in bringing reprogrammed Treg cell therapies to the clinic, and how will you overcome them?
We need clinical trials to better understand the behavior of reprogrammed Treg cells after their infusion into patients. We must understand how long they survive with stable function and how they can be further modified to better treat particular autoimmune diseases. For example, high production of IL-10 could be useful for the treatment of inflammatory bowel disease.
What future do you envision for autoimmune disease treatments?
The goal should be developing safe and effective treatments for patients, which requires disease-specific and stable suppression of autoimmune disease without adverse effects. We believe that we can achieve this with our reprogrammed Treg cells. In addition, we remain hopeful that we can develop drugs that can expand antigen-specific Treg cells in vivo upon exposure to antigens, such as upon administration of self-antigens targeted by the dysregulated immune system in autoimmune disease to achieve remission or resolution for these patients.
