Sakaguchi’s career is a testament to scientific perseverance. In the 1970s, the hypothesis concerning the existence of a distinct population of “suppressor T cells” remained contentious, largely due to a lack of reproducible experiments and definable molecular markers. The prevailing belief centred on the concept of “central immune tolerance”, in which autoreactive T cells were eliminated from the thymus, and this alone was thought sufficient to prevent T cells from reacting against self-tissues. Early clues emerged when researchers observed that neonatal mice subjected to thymectomy developed profound lymphopenia followed by aggressive autoimmune diseases, hinting that thymus-derived lymphocytes were essential for preventing self-directed immune activation.⁶ However, the identity and characteristics of these “suppressor” cells remained elusive. Throughout the 1970s and 1980s, mounting scepticism stalled progress, and the “suppressor” cell hypothesis was dismissed as a misleading artefact of early experimentation.

Amid this uncertainty, Sakaguchi remained steadfast in his conviction that the immune system must possess a regulatory compartment, and he began his investigations in 1979. The breakthrough came in 1995, while he was at the Aichi Cancer Centre Research Institute in Japan, with the publication of his landmark paper “Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune disease”, which identified a previously unrecognised subset of T lymphocytes defined by the CD4⁺CD25⁺ phenotype. This study demonstrated that depletion of these cells in experimental mice led to severe autoimmune diseases such as thyroiditis and polyarthritis.⁷ The “brakes” of the immune system were revealed—the cells now known as regulatory T (Treg) cells.

Once the suppressive capacity of Treg cells was established, attention turned to the next question: what molecular mechanism underlies their development? The parallel contributions of co-laureates Mary Brunkow and Fred Ramsdell proved pivotal. Investigating the fatal autoimmune phenotype of the “scurfy” mouse strain, they identified FOXP3 as the causative gene and subsequently linked the absence of a functional FOXP3 gene in humans to the development of IPEX syndrome, a fatal disorder of immune dysregulation.^9,10 By revealing the genetic basis of Treg cell deficiency, their work laid the groundwork for dissecting the FOXP3 targetome. This is the network of genes regulated by FOXP3 that governs Treg cell development, lineage stability, and suppressive function, thereby establishing translational pipelines for human disease. Two years later in 2003, Sakaguchi’s team demonstrated that FOXP3 encodes the transcription factor crucial for the development and function of Treg cells, publishing these findings in “Control of Regulatory T cell development by the transcription factor FOXP3”.¹¹ This discovery was soon independently corroborated by Fontenot et al., who showed that FOXP3 programmes the development and suppressive function of CD4⁺CD25⁺ Treg cells, further establishing FOXP3 as the master regulator of immune tolerance.¹² Together, these findings defined the cellular and genetic framework of peripheral immune tolerance, firmly securing Treg cells as a cornerstone of modern immunology (Figure 3). The elucidation of Treg cell biology marked a turning point, bridging fundamental immunological theory with emerging avenues for therapeutic innovation.

The journey from discovery to effective therapy is neither simple nor guaranteed. Following the announcement of the Nobel Prize, Sakaguchi expressed in an interview his hope that this research would inspire immunologists and clinicians to use Treg cells to “treat immunological diseases, control cancer immunity, or safer organ transplantation to prevent organ rejection”.¹³ Recent studies reveal that human Treg cells are phenotypically and functionally diverse, and a deeper understanding of their subset, ontogeny, and mechanism of suppression is essential to harness their therapeutic potential safely in autoimmune disease, transplantation, infection, and cancer.¹⁴

Although no Treg-based therapies have yet entered routine clinical practice, the field is advancing rapidly, with emerging clinical studies demonstrating the therapeutic potential of harnessing Treg cells. Notably, the MIROCALS trial investigated the use of low-dose interleukin-2 (IL-2LD) to selectively expand Treg cells in patients with amyotrophic lateral sclerosis (ALS) with the aim of improving survival. IL-2LD consistently increased circulating Treg cells and reduced inflammatory markers such as plasma CCL2. Adjusted analyses revealed a significant reduction in mortality among patients treated with IL-2LD after accounting for disease heterogeneity, underscoring the feasibility of immune modulation in neurodegenerative disease.¹⁵

In parallel, the engineering of Treg cells into chimeric antigen receptor T regulatory (CAR-Treg) cells represents an emerging approach to precisely suppress inflammation in targeted tissues.¹⁶ Conversely, selectively disabling tumour-protective Treg cells could enhance anticancer immunity. Tumour-infiltrating regulatory T (TI-Treg) cells suppress antitumour responses and promote cancer progression, and recent studies have identified CCR8 as a molecule highly expressed on these TI-Treg cells. This discovery positions CCR8-targeted therapies as a promising strategy to enhance antitumour responses while minimising immune-related toxicity.¹⁷