Nobel Prize in Physiology or Medicine 2025

The transcriptional regulators Foxp3 and Aire have key functions in self-tolerance. New studies emphasize potential links between Aire-expressing thymic stromal cells and the development of Foxp3-expressing regulatory T cells.

In this article, the authors describe the development, phenotype and suppressive function of human regulatory T cell populations. There has been much emphasis on the clinical use of these cells, and the associated progresses and pitfalls are discussed here.

Recent progress has revealed the molecular basis of how self-reactive T cells are normally generated in the immune system and differentiate into autoimmune effector T cells and how they are controlled by central and peripheral mechanisms of self-tolerance. There is also evidence that target tissues and cells in autoimmune disease have different sensitivities to immune mediators. Here we describe how these basic findings can be clinically translated to re-establish self-tolerance in individuals with autoimmune disease.

This study identifies 17 strains of human-derived Clostridia capable of inducing the accumulation and functional maturation of regulatory T cells; it is suggested that these strains may be useful candidates for the future development of oral bacterial therapeutics to treat human inflammatory disorders.

In this Viewpoint article, several experts share their thoughts on the plasticity and stability of regulatory T cells, discussing the recent advances in our understanding of the transcriptional and epigenetic regulation of this important T cell subset, as well as the therapeutic implications of this research.

Regulatory T (T_REG) cells can be subdivided into functional subsets. In this Review the authors apply advances in our understanding of mouse and human T_REG-cell biology to outline methods for T_REG-cell expansion and regulation. These techniques, which include antigen-specific expansion in vitro and in vivo, could soon be used to treat patients with autoimmune rheumatic diseases.

The molecular cloning of the forkhead box P3 (FOXP3) gene led to a renaissance in the field of suppressor T cells (now known as regulatory T cells). In this Timeline article, the authors describe the key events that demonstrated the importance of FOXP3in immune regulation, starting with the discovery of the scurfy mouse some 65 years ago.

Thymic regulatory T (T_reg) precursors undergo a distinct developmental pathway. Sakaguchi and colleagues show the chromatin organizer Satb1 is required for establishing the super-enhancer chromatin landscape of T_reg cell–specific signature genes before Foxp3 expression.

Fred Ramsdell and Alexander Rudensky revisit the discovery of the Foxp3 gene and its foundational role in the differentiation and function of regulatory T cells.

Here, the authors describe regulatory T (T_reg) cell development and function and discuss how molecular anomalies or genetic variations in T_reg cells contribute to autoimmune and inflammatory diseases. They also discuss how T_reg cells can be exploited to treat kidney diseases and to induce immune tolerance, particularly in kidney transplantation.

The RBPJ–NCOR repressor complex is identified as a negative regulator of FOXP3 expression through modulation of histone acetylation in induced regulatory T cells.

A fine balance is needed for T_reg cells to enable immune responses to pathogens without triggering autoimmunity. Data now show that thymus-derived self-peptide-specific T_reg cells suppress conventional T cells during infection, but enable immune responses to pathogen-derived peptides, thus promoting self–nonself discrimination.

Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi discovered cells that protect the body from autoimmune diseases.

Regulatory T cell therapies have shown promise for treating autoimmune diseases and aiding transplantation. We summarize a recent NIAID/HESI-sponsored workshop that addressed key issues in non-clinical and clinical development vital to advancing this immune tolerance paradigm.

This Review by Imianowski et al. outlines the various contributions that regulatory T cells, present in the tumour microenvironment, make towards tumour progression and highlight the ways in which they represent attractive next-generation immunotherapeutic targets.

Type 1 diabetes mellitus affects 8.5 million people globally and is characterized by autoimmune destruction of pancreatic β cells. This Review discusses cell replacement therapies for T1DM and outlines the challenges and future directions

Regulatory T cells keep the immune system in check to maintain homeostasis and restrain inflammation. This Review discusses strategies to harness these cells therapeutically for autoimmunity, transplant tolerance or cancer, for example, by boosting their endogenous function, depleting them or administering them as engineered cell-based therapies.

Graves disease, an autoimmune disease characterized by an enlarged and overactive thyroid gland, is the most common cause of hyperthyroidism in iodine-sufficient areas. In this Review, the authors describe the epidemiology, pathogenesis, and conventional treatment of Graves hyperthyroidism and Graves orbitopathy and discuss advances that have enabled development of novel treatment modalities.

Coeliac disease is an autoinflammatory disease, with the only available treatment being a lifelong gluten-free diet. Alternative therapeutic approaches are needed. This Review explores the concept of tolerance-inducing therapies for coeliac disease, highlighting the underlying mechanisms, progress, challenges and future directions.

After decades of frustration and failed attempts, scientists might finally be on the cusp of developing therapies to restore immune ‘tolerance’ in conditions such as diabetes, lupus and multiple sclerosis.

In this Review, the authors discuss the origins of regulatory T (T_reg) cells in the periphery and the mechanisms by which T_reg cells are induced, as well as the regulation of the suppressive function of these cells. Moreover, they examine evidence for and  mechanisms of T_reg cell dysfunction in common autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis.

Advances in understanding of the cause of autoimmune diseases and clinical data from novel therapeutic modalities such as chimeric antigen receptor T cells are providing evidence that it may be possible to re-establish immune homeostasis and, potentially, prolong remission or even cure autoimmune diseases. This article proposes a three-step ‘sequential immunotherapy’ framework for immune system modulation to help achieve this ambitious goal, and discusses existing drugs and those in development for each of the three steps.

Increasing evidence indicates that signalling networks activated downstream of oncogenic alterations contribute fundamentally to cancer immune evasion, including by promoting the accumulation of regulatory T (T_reg) cells and other immunosuppressive cells in the tumour microenvironment (TME). Herein, the authors discuss the mechanisms via which cancers engage T_reg cells to evade antitumour immunity, as well as the characteristics of T_reg cells in the TME and their roles in resistance to immune-checkpoint inhibitors. Considering these aspects, they propose the concept of ‘immuno-genomic cancer evolution’ for tumorigenesis and the related paradigm of ‘immuno-genomic precision medicine’, postulating that the specific characteristics of cancer, especially genetic profiles that correlate with particular immunosuppressive networks in the TME, are likely to inform individualized strategies for combining molecularly targeted agents with immunotherapies.

Regulatory T cells (T_reg cells) are controlled by a raft of transcription factors besides Forkhead box protein 3 (FOXP3). As detailed in this Review, these accessory transcription factors act alone or together with FOXP3 to coordinate T_reg cell specification and function, and account for heterogeneity of niche-specific T_reg cells.

Recent studies have highlighted the diversity and distinct nature of regulatory T cells in the intestine, where they must balance a multitude of signals from the microbiota and the diet to ensure immune homeostasis. But questions and controversies remain over their origins and regulation, as discussed here.

Shohei Hori recalls the early work that led to the identification of FOXP3 as the master regulator of regulatory T cells.

Pathogenic, long-lived memory cells of the immune system present a barrier to resolution of chronic inflammatory rheumatic diseases. Approaches to selectively eliminate these cells while sparing protective immune memory cells could restore immunological tolerance and achieve treatment-free remission.

Therapies based on adoptive cellular transfer of regulatory T (T_reg) cells are currently undergoing clinical trials for autoimmune diseases, graft-versus-host disease and the prevention of transplant rejection. This Review provides an overview of T_reg cell biology and discusses the latest approaches to enhance T_reg cells for therapeutic purposes.

In this Review, Thomson et al. describe the immunobiology underlying liver graft tolerance and failure, and discuss therapeutic approaches for minimization or withdrawal of anti-rejection immunosuppressive drug therapy post transplantation.

Our increased understanding of how regulatory T cells suppress immune responses has led to their use in early-phase clinical trials for inflammatory disorders, with promising results. This Review describes the key advances and prospects in designing and implementing regulatory T cells as multifaceted, adaptable smart therapeutics in autoimmunity and transplantation.

The suppression of excessive immune responses by infusion of regulatory T cells would require a product of high purity, adequate ex vivo expansion and functional stability. A description of the process to obtain an autologous cell product fulfilling these characteristics paves the way to develop clinical trials in humans.

The next challenge in rheumatoid arthritis (RA) therapy is the maintenance of disease remission with a minimal-treatment regimen. In this Review the authors propose that this goal could be achieved by restoring a state of immune tolerance and discuss antigen-independent and antigen-specific approaches for the induction of tolerance in the treatment of RA.

Asian researchers have been at the forefront of many topics in the field of Rheumatology, from the identification of disease entities that were first observed in the region to the establishment of the field of osteoimmunology. In this Review, Yamano and Nishioka highlight the ongoing contribution of Asian researchers to our understanding and treatment of rheumatic diseases.

It is shown that mice deficient for β₈ integrin develop colitis, and that β₈ needs to be expressed by dendritic cells rather than T cells for colitis to develop. In addition, a decrease of T cells in the gut but not adjacent lymph nodes in diseased animals is shown. It is concluded that αVβ8-mediated integrin activation of dendritic cells is essential for prevention of colitis-inducing immune dysfunction.

Inflammation plays a detrimental role in ischemic stroke. Now, Roland Veltkamp and his colleagues show that endogenous immunomodulatory T regulatory cells play a key part to dampen inflammation after stroke.

In these new reports, three different research groups independently find that various T cell populations are crucial mediators of obesity-induced metabolic dysfunction. They also show that pharmacological approaches that target these T cells are beneficial, thus opening the door to possible new therapeutic approaches to treating obesity-related diseases such as diabetes (pages 846–847, 914–920 and 921–929).

Regulatory T cells are characterized by the expression of Foxp3, however, how the expression of this protein is controlled is unclear. Here, the authors show that the nuclear orphan receptor, Nr4a2, is a transcriptional activator of Foxp3, and suggest that it is required for the function of regulatory T cells.

Thymus-derived regulatory T cells are activated by recognition of peripheral self antigen, persist in the target tissue on cessation of antigen exposure, and respond to re-exposure to self antigen with enhanced functional activity.

Germinal center B cell development is promoted by T follicular helper cells. Chen Dong and his colleagues show that Foxp3⁺ regulatory T cells expressing Bcl6 and CXCR5, two molecules highly expressed in T follicular helper cells, are present in humans and mice and arise from natural regulatory T cells. In vivo, these CXCR5⁺Bcl6⁺ regulatory T cells modulate germinal center responses.

Follicular helper T (T_FH) cells provide survival and selection signals to germinal center B cells. Here, Carola Vinuesa and colleagues describe a regulatory T cell subset that co-opts the differentiation program of T_FH cells and limits their numbers in vivo. Ablation of these T_FH-like, T regulatory cells alters the number of antigen-specific B cells suggesting regulatory T cells modulate germinal center responses.

Successful pregnancy requires immune tolerance against paternal antigens expressed by the fetus; here pregnancy is shown to stimulate the selective accumulation of maternal immune-suppressive regulatory T cells with fetal specificity that are retained post-partum, which may explain the protective benefits of prior pregnancy against pre-eclampsia and other complications in subsequent pregnancy.

By using high-throughput sequencing of T-cell receptors, this study shows that thymus-derived regulatory T (T_reg) cells constitute most T_reg cells in all lymphoid and intestinal organs, including the colon, suggesting that thymic T_reg cells and not induced T_reg cells dominantly control tolerance to the gut’s antigens such as commensal microbiota.

The differentiation of naive CD4 T cells into T-helper-cell subsets is thought to be influenced by factors in the T-cell environment. Martin et al.reveal that cell intrinsic differences also determine lineage commitment and show that cells with the highest avidity for self are most likely to become induced regulatory T cells.

The gut microbial metabolite butyrate is shown to induce the differentiation of colonic T regulatory cells in mice and to ameliorate the development of colitis; it also increases histone H3 acetylation at the Foxp3 promoter.

In mice, provision of butyrate—a short-chain fatty acid produced by commensal microorganisms during starch fermentation—facilitates extrathymic generation and differentiation of Foxp3⁺ regulatory T cells, demonstrating that metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells.

The alarmin interleukin-33 is constitutively expressed at barrier sites and released in response to tissue damage; here, the IL-33 receptor ST2 is shown to be preferentially expressed on colonic regulatory T cells, where it promotes regulatory T-cell function and adaptation to the inflammatory tissue environment.

Fat-resident regulatory T cells (fT_reg cells) accumulate in adipose tissue of mice as a function of age, but not obesity; mice without fT_reg cells are protected against age-associated insulin resistance, but remain susceptible to obesity-associated insulin resistance and metabolic disease, indicating different aetiologies of age-associated versus obesity-associated insulin resistance.

Nanoparticles coated with autoantigenic peptides bound to MHC class II molecules suppress established autoimmune disease by inducing antigen-specific T_R1-like regulatory T cells in mouse and humanized mouse models.

John Harty and colleagues report that, in mouse models of malaria, regulatory T cells expand, as in humans, and inhibit conventional T cells and germinal center B cells, thereby impairing protective responses against blood-stage disease. Timed blockade of the inhibitory receptor CTLA-4 cured infection in mice and promoted cross-protective blood-stage immunity against a different Plasmodium species.

A human anti-IL-2 antibody that selectively expands regulatory T cells is developed in this study for clinical applications aiming to mitigate autoimmune and inflammatory disorders and to promote transplant tolerance.

In a mouse model of ischaemic stroke, regulatory T cells infiltrate the injured brain in response to the chemokines CCL1 and CCL20 and suppress excessive astrogliosis via the production of amphiregulin.

Bacteriotherapy using gut-derived bacteria from healthy human infants, but not infants with food allergies, suppresses food allergy symptoms in mice via induction of Foxp3 + Rorγt + regulatory T cells

The secondary bile acid 3β-hydroxy-deoxycholic (isodeoxycholic) acid, produced by gut bacteria, promotes the generation of colonic extrathymic regulatory T cells, whose immunosuppressive activities are known to be essential for intestinal health.

Both dietary and microbial factors influence the composition of the gut bile acid pool, which in turn modulates the frequencies and functionalities of RORγ-expressing colonic FOXP3⁺ regulatory T cells, contributing to protection from inflammatory colitis.

Visceral adipose tissue contains populations of regulatory T cells that exhibit sexual dimorphism, determined by the surrounding niche, and differ between male and female mice in terms of cell number, phenotype, transcriptional landscape and chromatin accessibility.

The tumour microenvironment is low in glucose and high in the alternative metabolite lactate, which regulatory T cells are shown here to use, maintaining their ability to suppress effector immune cells.

Identification of a metabolic checkpoint involving lipid signalling that is specific to regulatory T cells (T_reg cells) in the tumour microenvironment raises the possibility of targeting this checkpoint for treatment of cancer.

Single-cell transcriptomics analyses of pretreatment and post-treatment peripheral blood mononuclear cells from patients treated with CD19 chimeric antigen receptor (CAR)-T products reveal a role for CAR-T regulatory cells in treatment relapse.

Single-cell proteomic profiling of circulating CAR T cells in patients treated with CD19-CAR shows that CD4⁺Helios⁺ CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity.

Single-cell transcriptomic and epigenetic analysis has enabled the identification of Thetis cells, a class of RORγt⁺ antigen-presenting cells with a key role in the differentiation of commensal microbiota-induced peripheral regulatory T cells.

Induction of T regulatory cells by gut microbes is mediated by antigen-presenting RORγt⁺ cells, unlike that of T follicular helper and T helper 17 cells, which requires different cell types.

ILC3s expressing MHC class II control the fate of inflammatory versus tolerogenic T cells that respond to the microbiota by selecting for antigen-specific RORγt⁺ T_reg cells and against T_H17 cells, establishing intestinal homoeostasis.

In mouse and rat models of Parkinson’s disease, co-transplanting regulatory T cells (T_reg cells) improves the survival of grafted midbrain dopamine neurons in cell therapies by reducing the inflammatory response caused by surgical injury.

A high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients with non-small cell lung cancer treated with atezolizumab plus tiragolumab, but not with atezolizumab alone.

Ptacin et al. utilize a semi-synthetic microbial platform with an expanded genetic code to discover a PEGylated IL-2 compound that stimulates Tregs, with minimal effects on effector populations. Studies in mice and primates demonstrate Treg stimulation and support development of this compound for the potential treatment of autoimmune diseases.

Adoptive transfer of regulatory T (Treg) cells holds promise for the treatment of inflammatory diseases, but maintaining a therapeutic capacity is challenging. Here, the authors show that engineering Tregs to express an IL-2 partial agonist enhances Treg persistence and suppression of inflammation in mouse models, representing a potential optimization for Treg therapy.

Obstetric complications are less frequent in subsequent than in first pregnancies, and one potential difference is immunological adaptation of the mothers. Here authors compare the immunological landscape of the uterine microenvironment in mice during first and subsequent pregnancies to find that tolerogenic regulatory T cells recognising foetal antigens accumulate in subsequent pregnancies to enable better foetal development and overall pregnancy outcome.