Immune modulation, immune homeostasis and diseases: Milestone findings by 2025 Nobel Laureates in Physiology or Medicine

The 2025 Nobel Prize in Physiology or Medicine honors three scientists for their work in identifying the cellular and molecular basis of peripheral immune tolerance. This mechanism prevents the immune system from attacking the body while defending against pathogens. 1. Profiles of the laureates and summary of their discoveries Mary Brunkow: Genetic Tracing Expert Brunkow is a molecular biologist at the Institute for Systems Biology in Seattle, Washington. With a sustained focus on the genetic causes of immune diseases, she has made seminal contributions to gene mapping and functional studies. Fred Ramsdell: Immunotherapy Pioneer Ramsdell is a scientific adviser at Sonoma Biotherapeutics in Seattle, Washington. He has been involved in developing T cell-modulating immunotherapies and has played a pivotal role in translating basic discoveries into clinical practice. Shimon Sakaguchi: The Father of Regulatory T Cells (Tregs) Sakaguchi, a distinguished professor at Osaka University’s Immunology Frontier Research Center, has been hailed the “father of Tregs.” He is a pioneer in the field, and his work has fundamentally transformed our understanding of immunoregulatory mechanisms. At the prize announcement, Nobel committee member Marie Wahren-Herlenius remarked that the trio “have provided fundamental knowledge of how the immune system is regulated and how immune responses are kept in check so that the body can combat all imaginable microbes while avoiding autoimmunity”.[1] Samantha Bucktrout (Greywolf Therapeutics), who previously collaborated with Ramsdell, added that these foundational discoveries launched an entire field and have catalyzed a pipeline of therapies for autoimmune diseases now in early clinical development. “If it wasn’t for these initial findings, we would never be at this place now where we can talk about cures,” she said.[1] Autoimmune disorders, including type 1 diabetes, arthritis, and multiple sclerosis, affect approximately one in ten people.[2] 2. The laureates’ key scientific contributions: From Tregs to Forkhead Box protein P3 (FOXP3) In 1995, Sakaguchi and his colleagues demonstrated that the selective depletion of CD25+ T cells in mice triggered severe multi-organ autoimmunity, proving that CD4+CD25+ T cells are indispensable for maintaining self-tolerance.[3] This was the first clear evidence of “suppressor” T cells, which were later termed Tregs.[4] By 2000–2001, Brunkow and Ramsdell had identified Foxp3 as the genetic basis of the scurfy mouse’s fatal autoimmune phenotype.[5,6] In addition, mutations in its human ortholog, FOXP3, were found to cause IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. These findings indicated that FOXP3 plays a role in immune regulation and tolerance.[4,6,7] In 2003, Sakaguchi’s group confirmed that FOXP3 is both necessary and sufficient for Treg development and function.[8] Within two years, the critical role that FOXP3 plays in Treg development and function was strongly substantiated.[9] By connecting the functional identity of Tregs to their transcriptional programming, Sakaguchi and his colleagues established the cellular and molecular architecture of peripheral immune tolerance. Collectively, the laureates provided a chain of evidence showing the effect of a master regulatory gene on a functional T-cell population. By determining the cellular and molecular basis of peripheral immune tolerance, they opened the door to the development of tolerance-oriented immunotherapies. 3. Infection and immunity: Optimizing pathogen clearance and minimizing self-damage The human immune system is a highly regulated biological network that continuously surveils for and eliminates invading bacteria, viruses, and other pathogens while maintaining tolerance to self. Among its many cellular components are T cells, which play vital roles in adaptive immunity. Through clonotypic T-cell receptors (TCRs), CD8+ cytotoxic T lymphocytes (CTLs) recognize pathogen-derived peptides presented by major histocompatibility complex (MHC) class I on infected or transformed cells, whereas CD4+ helper T cells recognize peptides presented by MHC class II on antigen-presenting cells (APCs). Upon antigen recognition, CD4+ T cells coordinate the immune response by secreting cytokines and activating other effector populations, including CD8+ CTLs, which in turn directly induce the death of target cells, principally via perforin/granzyme release and death-receptor pathways.[4] T cells are generated and selected in the thymus, a primary lymphoid organ. CD34+ hematopoietic stem and progenitor cells in the bone marrow give rise to thymus-seeding progenitors that enter the thymus and, through staged differentiation, undergo somatic V(D)J recombination at the TCRα and TCRβ loci, which results in surface expression of a unique clonotypic αβ TCR. Each mature T cell expresses a TCR specific for a single antigen. The combinatorial use of V, D, and J segments and the occurrence of junctional diversification (i.e., nucleotide additions and exonuclease trimming) together create a potential repertoire of 1013–1015 distinct αβ TCRs, and each person typically generates 107–108 unique clonotypes. While this process equips the immune system to recognize virtually any exogenous antigen, it also generates T cells with TCRs that spuriously recognize the body’s own tissues. Consequently, the body maintains immune self-tolerance primarily through central and peripheral immune tolerance mechanisms, which eliminate and restrain autoreactive T cells (Figure 1).[8]Figure 1: The mechanisms underlying the maintenance of immune tolerance. (A) Activation of antigen-specific cytotoxic T lymphocytes against foreign pathogens. (B) When the host’s immune system is insufficient to quickly clear the infection of foreign pathogens, to avoid self-harm, Treg cells down-regulate the activity of CTLs to coexist peacefully. CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; pMHC: Antigen peptide-MHC molecule complex; TCR: T cell receptor; IL: Interleukin: CD: Cluster of differentiation; CTL: Cytotoxic T lymphocyte; Th1 cell: T helper cell 1; Treg: Regulatory T cell; MHC: Major histocompatibility complex: LAG3: Lymphocyte activation gene-3; TIGIT: T cell immunoreceptor with immunoglobulin and ITIM domain; ADP: Adenosine diphosphate; ATP: Adenosine triphosphate; TGF-β: Transforming growth factor-β: A2AR: Adenosine A2A receptor; DC: Dendritic cell; APC: Antigen-presenting cell; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death ligand 1.As early as the 1980s, it was widely accepted that autoimmune responses were prevented by T cells undergoing central immune tolerance in the thymus.[10] During thymic maturation, developing T cells are subjected to a stringent selection process: clones that recognize self-peptide–MHC complexes with excessively high affinity are induced to undergo apoptosis (negative selection) or diverted into the thymus-derived Treg (tTreg) lineage. Although the thymus efficiently purges many autoreactive T cells via central immune tolerance, a substantial fraction of such cells exits the thymus. Complementary peripheral immune tolerance mechanisms have evolved to reduce the threat posed by circulating autoreactive T cells and to maintain self-tolerance.[11] The three laureates were awarded the 2025 Nobel Prize in Physiology or Medicine for their outstanding contributions to the identification of peripheral immune tolerance. Peripheral immune tolerance function as a finely tuned “firewall,” ensuring that immune activity is reduced when external threats have been cleared, which helps limit collateral damage to the body’s own tissues. Tregs serve as the immune system’s “safety valve,” tempering excessive immune activation and preventing misguided attacks on the host. Tregs can induce myeloid-derived suppressor cells and modulate antigen presentation. They express CD39 and CD73, which convert ADP or ATP to adenosine, thereby shaping the duration, intensity, and biochemical nature of purinergic signaling to immune cells. Finally, metabolites produced by the gut microbiota, including short-chain fatty acids (e.g., butyrate), exert major effects on immune function. For a T cell to be fully activated (i.e., to proliferate, differentiate, and survive), it must receive two signals: one via its TCR (the first signal) and a costimulatory (second) signal.[7] The two signals must be received in order (the first signal, then the second signal). When the costimulatory pathway is blocked, antigen-specific apoptosis and clonal anergy result, which promote immune tolerance. For example, in animal models of autoimmune disease and organ transplantation, immune tolerance can be induced by interrupting costimulation with monoclonal antibodies, soluble high-affinity receptors for CD80 and CD86, or cytotoxic T-lymphocyte-associated protein 4(CTLA-4)-Ig.[12,13] Mechanism of peripheral immune tolerance is the presence of specialized cell populations that suppress inadvertent pathological autoimmune responses.[14] These populations include Tregs, in induced Treg (iTreg) cells, type 1 regulatory T (Tr1) cells that secrete interleukin (IL)-10, and T helper type 3 cell (Th3) cells that secrete transforming growth factor beta (TGF-β).[15] Among these cell types, Tregs are the best characterized. They are a subset of self-reactive CD4+ T cells that express the master transcriptional repressor FOXP3. Genetic mutations that impair the function of FOXP3 (as observed in scurfy mice and in patients with IPEX syndrome) and pharmacologic interference with FOXP3 activity have both been shown to result in severe autoimmune disease.[16,17] In addition to arising during thymic negative selection, Tregs can be generated in peripheral lymphoid organs when naive CD4+ T cells encounter antigens within an immunosuppressive milieu.[18] Under certain conditions, antigen presentation induces stable FOXP3 expression and converts conventional T cells (Tconvs) into peripherally derived Tregs (pTregs). Studies have shown that Tregs can recognize commensal bacteria that exhibit the features of host antigens.[19] This diversifies the Treg repertoire and effectively curtails inflammatory responses against such bacteria that have a positive relationship with the host. Additionally, pTregs can recognize modified proteins, such as citrullinated peptides, hybrid peptides, and phosphorylated proteins, which are commonly present in autoimmune diseases but are absent from the thymus.[20] Together, tTregs, pTregs, IL-10-producing Tr1 cells, and TGF-β-producing Th3 cells act in concert to generate the broadest possible antigen-recognition repertoire for restraining pathogenic autoreactivity.[21] In summary, APCs act with Tregs and other suppressive T-cell subsets to restrain immune responses and thus mediate peripheral immune tolerance. These cells develop in response to a variety of cell-surface molecules and soluble mediators, including factors regulated by Tregs themselves. Tregs and other regulatory cells secrete cytokines (e.g., IL-10, IL-35, and TGF-β) and other soluble mediators involved in metabolism. Collectively, these and other regulatory factors act on APCs to promote the generation of Tr1 cells and Tregs or to directly influence pathogenic T cells by altering their differentiation, trafficking, and effector functions.[22] 4. The emerging role of tregs in tissue regeneration and their regulatory mechanisms In addition to their suppressive role in peripheral immune tolerance, Tregs can mediate tissue repair. Canonical mechanisms, including IL-10 and TGF-β secretion, CTLA-4-mediated checkpoint engagement, high-affinity IL-2 consumption via CD25, and CD39/CD73-driven purinergic remodeling, position Tregs as attractive therapeutic targets for the treatment of autoimmune and inflammatory diseases by not only suppressing inflammation but also fostering subsequent tissue repair and regeneration.[23] Given that Tregs deliver pro-repair cues directly to epithelial, mesenchymal, and endothelial compartments, they can support the regeneration of lung, skin, gut, and central nervous system tissue after acute and chronic injury, creating opportunities in regenerative medicine. Mechanistically, Treg-derived amphiregulin (Areg) accelerates alveolar repair in viral lung injury independently of antiviral immunity, with Epidermal growth factor receptor (EGFR)-high mesenchymal subsets acting as proximal targets that propagate the mesenchymal-to-epithelial repair cascade. Hence, enhancing the Treg–Areg axis and tuning the tissue receptor landscape are potential strategies for pulmonary regeneration.[24] In ischemia–reperfusion and metabolic vasculopathies, Tregs, their conditioned medium, IL-10, and Areg promote endothelial tubulogenesis, supporting an immunoregulatory route to pro-angiogenic therapy.[25] Druggable switches have also been identified. For example, IL-18/IL-33, glucocorticoids, and selected neurotransmitters upregulate Treg repair programs, whereas Notch receptor 4 (Notch4) and the lipid-sensing receptor G protein-coupled receptor 174 (GPR174) restrain Areg induction and tissue restoration, suggesting that blocking Notch4 or GPR174 or providing IL-33 or related cues could amplify Treg-mediated regeneration.[26,27] Importantly, context-dependent Treg–stromal crosstalk occurs in chronic fibrosis and the tumor microenvironment. While it can mitigate inflammation and fibrogenesis, it may also be co-opted for matrix remodeling and angiogenesis, which underscores the need for pathology-specific control and rational combination strategies. Finally, visceral adipose tissue Tregs and IL-33+ mesenchymal cells constitute a metabolism–immune–repair axis, highlighting adoptive Treg strategies or revitalization of the IL-33–Treg pathway as potential interventions for treating insulin resistance and related metabolic diseases.[28] Clinically, the development of Treg-based therapeutics is advancing along two complementary tracks: i) pharmacologic in vivo expansion of natural Tregs (nTregs) and ii) adoptive transfer of Tregs expanded in vitro. The aim of both approaches is to restore durable, antigen-selective tolerance while minimizing broad immunosuppression. Since Tregs express high-affinity IL-2R (CD25), low-dose IL-2 regimens can be used to selectively expand Tregs in vivo while limiting the activation of natural killer (NK) cells and Tconvs, with promising clinical response data observed in graft-versus-host disease (GvHD), type 1 diabetes, alopecia areata, and Hepatitis C virus (HCV) -associated vasculitis. Likewise, given that Tumor necrosis factor receptor 2 (TNFR2) is more highly expressed on activated Tregs than on Tconvs, it is possible to expand nTregs in vivo and in vitro via TNFR2 stimulation, and this approach has shown promise in GvHD. The adoptive transfer methodologies involve purifying autologous circulating Tregs, expanding them in vitro via TCR stimulation and incubation with IL-2, and reinfusion. Naive nTreg populations can be expanded 500–2,000 fold, transferred cells can persist for more than one year, and early-phase trials (e.g., in type 1 diabetes) indicate that this approach is feasible and safe.[29] The next steps include determining whether antigen-specific Tregs generated via in vitro antigen stimulation outperform polyclonal Tregs generated via in vivo enrichment, and improving the manufacturing process to address the low Treg yields and expansion rate. To enhance the potency and durability of Tregs, as well as their capacity to target specific tissues, Chimeric antigen receptor-Tregs (CAR-Tregs) designed to target disease-relevant antigens are being developed.[29] 5. The dual functions of Tregs in hepatitis b virus (HBV) and human immunodeficiency virus (HIV) infection With an estimated 254 million people worldwide infected with HBV, this virus remains a pervasive global health challenge.[30] HBV can cause a wide spectrum of liver diseases, from asymptomatic and symptomatic acute hepatitis (including acute fulminant hepatic failure) to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Many chronically infected persons have mild liver disease with or or in chronic HBV infection to and is that the immune response induced by HBV disease and the of antiviral In the disease Tregs are that the liver from damage while viral and tumor During HBV they excessive inflammation and limit hepatocellular injury, fulminant this CD8+ and fibrogenesis, and to the of circulating and Tregs are in patients and with CD8+ CTLs and immune the natural of diseases, the of Tregs with the disease Treg are typically in patients with chronic hepatitis and and in patients with and liver which the and of Treg Mechanistically, Tregs induce a of via and soluble including checkpoint via generation through signaling through Lymphocyte Activation and T cell immune receptor with and ITIM that and of IL-10, and These mechanisms effector activation and maintain tolerance in the In the immunosuppressive effect is The of Tregs that in with expression of receptors (e.g., and (e.g., of or enhance effector T cell and of or In addition, When receptor 4 Tregs are by hepatic ligand ligand resistance is and CD8+ In Hepatitis a receptor 1 endothelial axis that Tregs into the and Tregs, that and are potential combinatorial Tregs also influence and to the microenvironment. 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Treg-based therapies must be to into the fibrosis and and (e.g., FOXP3 and and must be as well as that both and clinical By the of and it may be possible to the activity of Tregs while their suppressive effects on pathogen and tumor control and in viral and of and in the and of the and and the the from the and the of the for of