Therapeutic potential of Tregs

Key points

• The role of regulatory T cells (Tregs) in self-tolerance has become clear in recent years following the award of the Nobel Prize in Physiology or Medicine in 2025.
• Tregs contribute to immune self-tolerance and maintain tissue homeostasis; adding a chimeric antigen receptor (CAR) confers greater specificity and efficacy, according to early trials.
• The development of therapeutic Tregs represents an important addition to the exciting field of immune modulation.

The immune system’s ability to defend the host against a vast array of microorganisms while avoiding autoaggressive responses is an extraordinary feat. This is particularly remarkable given that the proteins of a pathogen are not categorically different from those of the host. Over recent decades it has become clear that this feat results from both deletion of self-reactive cells in the thymus and regulation of rogue T cells in the periphery. The 2025 Nobel Prize in Physiology or Medicine was awarded to Sakaguchi, Ramsdell, and Brunkow for the discovery of naturally occurring regulatory T cells (Tregs), the specialized T-cell population now recognized as central to peripheral tolerance.

In rat and mouse models, it had long been observed that immune tolerance could be transferred by injecting T cells from a tolerant animal into a naive animal (1). The cellular basis of this phenomenon became clearer through the work of the Nobel laureates, who identified a thymus-derived lineage of cells expressing the key transcription factor forkhead box P3 (FOXP3).

The working assumption is that thymically selected Tregs, specific for a variety of autoantigens, patrol peripheral tissues and are called into play when tissue inflammation is triggered by an invading pathogen. The Tregs thought to sustain self-tolerance in such situations are those specific for autoantigens expressed by the tissue in question. Given their capacity for linked and bystander suppression, it is remarkable that these Tregs can restrain autoreactive T cells in the inflamed tissue without unduly compromising the immune response against the invading pathogen.

It has become increasingly evident that Tregs not only prevent autoreactive responses but also play an important role in tissue repair and homeostasis. Tregs are heterogenous in phenotype and function, and they circulate and localize in different tissues (2). They respond to changes in their tissue microenvironment by modulating inflammatory responses and maintaining tissue homeostasis (3). However, it remains unclear precisely how Tregs respond to tissue damage or influence tissue fibrosis.

In their Frontiers in Science lead article, Bluestone et al. (4) outline the scientific and translational advances that are bringing the therapeutic use of Tregs closer to clinical reality (4). There is undoubtedly a substantial unmet clinical need for better means of suppressing unwanted immune responses in autoimmunity and organ transplantation. Pharmacological immunosuppressive drugs are effective in many settings, but are associated with multiple side effects, including increased incidence of cancer and opportunistic infections. In other disorders, such as severe rheumatoid arthritis and systemic sclerosis, these drugs provide only modest benefit, and few treatment options are available.

The therapeutic potential of Tregs is now being explored across a rapidly evolving field of research. Early clinical trials of polyclonal Tregs in kidney and liver transplant recipients demonstrated an acceptable safety profile and provided some tantalizing hints of efficacy in dampening the rejection response (5). However, animal models showed that conferring alloantigen specificity on the injected Tregs substantially increased their potency (6, 7). A very recent phase 1/2 trial of alloantigen-specific Tregs in human transplant recipients yielded partial success in achieving operational tolerance (8). According to interim results, following infusion of Tregs expressing a chimeric antigen receptor (CAR) specific for a human leukocyte antigen (HLA) expressed by the donor liver, several liver transplant recipients were weaned off calcineurin inhibitor immunosuppressive therapy and maintained stable transplant function on low doses of everolimus alone. Nonetheless, when the remaining low dose of immunosuppressive therapy was withdrawn, rejection ensued. This highlights an important point: Tregs are designed to control low-frequency autoimmune responses, but asking them to manage responses against HLA alloantigens, which are orders of magnitude higher in frequency, is a very tall order.

Although operational tolerance has yet to be achieved, early clinical studies have shown the potential for therapeutic Tregs to overcome several important translational challenges. They can persist in the circulation for at least 1 year after infusion and become enriched at the site of the relevant target antigen (e.g., the transplanted liver), potentially reaching levels sufficient to allow minimization of immunosuppressive drug use. They can also retain a stable phenotype—resembling native Tregs as judged by their surface markers and transcriptional profile—which is important for their function and safety.

These observations suggest that the therapeutic use of Tregs has a bright future in the context of autoimmune and inflammatory diseases. Preliminary results were recently reported from a small phase 1 study of CAR-Tregs specific for citrullinated proteins, which are highly expressed in patients with rheumatoid arthritis (9). Treatment led to rapid improvements in symptoms and reduced joint inflammation. Although these effects were temporary, they indicate the possible benefits of this approach.

In certain autoimmune diseases, CAR effector T cells with specificity for autoreactive B cells have generated intense interest. The first trial of this approach was reported in 2022 in patients with systemic lupus erythematosus (10), spawning several subsequent trials in related diseases. These successes parallel advances in the use of bi-specific T-cell engagers that harness the lytic function of T cells to kill autoreactive B cells. While these examples illustrate promising categories of therapeutics, even more may be gained by deploying Tregs, as opposed to T effectors, to target autoreactive B cells. Further trials e.g., United States national clinical trial (NCT) [NCT07473154] are targeting Tregs to the sites of immune activation in both lymphoid and peripheral tissues, aiming not only to arrest the immune response but also to help restore tissue homeostasis. This approach capitalizes on the ability of Tregs to mediate “bystander effects”, calming proinflammatory monocytes and even inhibiting fibroblast activation.

The development of therapies that manipulate the immune system is one of the most exciting advances in modern medicine. Harnessing Tregs and directing their attention to sites of autoimmune, alloimmune, and inflammatory responses—as highlighted by Bluestone et al. (4)—represents an important addition to this field.

Generative AI statement

The authors declared that generative AI was not used in the creation of this manuscript.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited and reviewed by: Pietro Ghezzi, Brighton and Sussex Medical School, United Kingdom