Feven Getachew
Junhui Hu
Mehdi Benamar- 1Division of Immunology, Boston Children’s Hospital, Boston, MA, United States
- 2Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- 3Department of Otolaryngology Head and Neck Surgery, Shanghai Key Laboratory of Sleep Disordered Breathing, Otolaryngological Institute of Shanghai Jiao Tong University, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 4Institute of Regenerative Medicine and Biotherapy, INSERM, University of Montpellier, Montpellier, France
Regulatory T (Treg) cells are essential for maintaining immune tolerance, preventing autoimmune responses, and supporting tissue repair. Tregs employ a flexible and diverse metabolic program that includes glycolysis, oxidative phosphorylation (OXPHOS), fatty acid oxidation, and lipid metabolism compared to conventional T cells, which largely rely on glycolysis to fuel their proliferation and function. This flexibility allows Tregs to adapt in different tissue environments while sustaining their suppressive activity. Thymic-derived (tTregs), peripheral (pTregs), and induced (iTregs) exhibit distinct metabolic profiles that influence their stability, proliferation, and suppressive capacity. These metabolic pathways are controlled by key regulators such as mTOR, LKB1, and Foxp3, while environmental cues, including nutrient availability, hypoxia, and microbiota-derived metabolites, further shape Treg function. Dysregulation of these pathways can compromise tolerance and contribute to immune-mediated diseases, chronic infections, cancer, and metabolic disorders. In this mini review, we summarize recent insights into the heterogeneity of Treg metabolism, highlighting how metabolic reprogramming underpins their immunoregulatory roles. We also explore therapeutic opportunities for targeting Treg metabolism and discuss future directions leveraging single-cell and spatial technologies to map context-specific metabolic programs in vivo.
Introduction
Each organ system in the human body presents specific functions, and the immune system is no exception. One of its primary roles is to protect against invasion and destruction by pathogens distinguished as “non-self” antigens, while simultaneously tolerating host-derived “self” components (1–3). A breakdown of this delicate balance can result in the loss of immune tolerance and the initiation of aberrant immune responses against self-tissues, which are characteristic of autoimmune diseases (2, 4). Treg cells, a specialized subset of CD4+ T cells, play an essential role in controlling this balance by suppressing excessive immune responses and promoting immune homeostasis (3). Tregs represent approximately 5–15% of peripheral CD4+ T cells and are characterized by expression of CD25, the transcription factor Foxp3, and low or absent CD127 in humans (3, 5). Importantly, Tregs can exert suppressive effects by several immunosuppressive mechanisms, including the secretion of immunoregulatory cytokines, cytotoxicity, metabolic modulation, and modulation of antigen-presenting cells’ function (6, 7). Beyond immunosuppression, Tregs also contribute to tissue repair (8–13). The discovery of Tregs and their reliance on Foxp3 was initially highlighted by studies of the scurfy mouse and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in humans, both caused by mutations in the Foxp3 gene (5, 14–16). These observations established Foxp3+ Tregs as indispensable guardians of self-tolerance. More recently, it has become clear that their function depends not only on transcriptional regulation but also on specialized metabolic programs (17, 18). Conventional T cells predominantly favor glycolysis and glutaminolysis to support rapid proliferation and effector functions (19, 20). In contrast, Tregs exhibit a more versatile metabolic program, dynamically shifting between glycolysis, oxidative phosphorylation (OXPHOS), lipid metabolism, and amino acid utilization depending on their differentiation state and microenvironmental cues (17, 19). This metabolic plasticity underpins their ability to exert diverse suppressive functions. In this mini review, we discuss the molecular underpinnings of Treg metabolism, highlight the heterogeneity between Treg subsets, and consider the implications of metabolic regulation in health and disease.
Heterogeneity of Treg metabolism
Thymic versus peripheral Tregs
Thymic Tregs (tTregs) originate during T cell ontogeny in the thymus and are selected for high-affinity recognition of self-MHC molecules without crossing the threshold for deletion. Peripheral Tregs (pTregs) arise from conventional CD4+ T cells in vivo under tolerogenic conditions, while induced Tregs (iTregs) are generated in vitro from naive CD4+ T cells cultured in the presence of IL-2 and TGF-β (21, 22). Interestingly, tTregs and iTregs display distinct metabolic signatures (Figures 1A, B). Indeed, mouse tTregs cultured in IL-2 for three days exhibit high glycolytic activity, whereas iTregs induced with IL-2 and TGF-β display reduced glycolysis. Enhanced glycolysis in tTregs is associated with increased expression of glycolytic regulators such as HK2, Glut1, and Glut3. Addition of TGF-β to tTregs suppresses glycolysis, as indicated by reduced extracellular acidification rate (ECAR), decreased expression of glycolytic enzymes, and inhibition of the PI3K/Akt/mTOR pathway, which collectively impair their proliferation and suppressive capacity (23). In contrast, CD4-specific Glut1 deletion reduces conventional Foxp3− CD4+ T cells but has little effect on Foxp3+ Tregs, suggesting that tTregs can rely on alternative metabolic pathways (24). These findings highlight the complexity of Treg metabolic requirements.
Figure 1. Heterogeneity of Treg metabolism. (A) Thymic Treg (tTreg) cells engage glycolysis through upregulation of Glut1 and Glut3, enhancing glucose uptake and activating PI3K–Akt–mTORC1 signaling. This pathway induces expression of hexokinase 2 (HK2), a rate-limiting enzyme in glycolysis. In peripheral tissues, antigen-driven activation of tTreg cells promotes mTOR–IRF4 signaling, further enhancing glycolysis and nucleotide metabolism. (B) Suppressive induced Treg (iTreg) cells (left) exhibit elevated Foxp3 expression, which reprograms cellular metabolism toward oxidative phosphorylation (OXPHOS). Upregulation of fatty acid–binding protein 5 (FABP5) facilitates mitochondrial fatty acid transport, promoting fatty acid oxidation (FAO) and increasing acetyl-CoA availability for OXPHOS. In contrast, proliferative iTreg cells (right) display TLR-dependent PI3K–Akt–mTORC1 activation, leading to increased Glut1 and HK2 expression, enhanced glycolytic flux, and induction of HIF-1α, which drives transcription of glycolytic genes. (C) Peripheral Treg (pTreg) cells (left) undergo Foxp3-dependent metabolic reprogramming toward OXPHOS, accompanied by activation of the mevalonate pathway via upregulation of liver kinase B1 (LKB1). Additionally, pTreg cells exhibit enhanced FAO through CD36-mediated uptake of long-chain fatty acids.
Glycolysis in Treg proliferation and function
Glycolysis provides rapid ATP and biosynthetic intermediates necessary for cell growth. Previous studies have emphasized the importance of mTOR activation as an evolutionarily conserved requirement for T cell development and differentiation (25, 26). TLR1 and TLR2 signaling induce the PI3K–Akt–mTORC1 axis, which enhances mouse iTreg cells’ proliferation and glycolytic activity, as measured by increased ECAR and Glut1 expression (Figure 1B). However, these highly glycolytic iTregs show reduced suppressive capacity (27). Foxp3 itself appears to antagonize glycolysis (17). Ectopic expression of Foxp3 in naive T cells reduces glucose uptake, GLUT1 and HK2 expression, and Akt/mTOR phosphorylation, while increasing oxygen consumption and pyruvate oxidation. This metabolic shift diverts cells toward OXPHOS, supporting suppressive function rather than effector activity (27). Moreover, HIF-1α, a transcription factor stabilized under hypoxic and glycolytic conditions, favors Th17 differentiation while inhibiting Treg generation, illustrating the reciprocal balance between metabolic and immunological fates (28). While mTOR signaling is dispensable for iTreg differentiation in vitro (29), in vivo studies reveal its necessity for maintaining pTregs. It also promotes activation of peripheral tTreg to effector Treg status through regulation of IRF4, particularly in mucosal tissues which further promote glycolysis and nucleotide metabolism (30)(Figure 1A). In human Tregs, glycolysis is also critical. Freshly isolated, unmanipulated human Tregs demonstrate a higher dependence on glycolysis and express higher levels of mTOR compared to Tconv cells. Inhibition of mTOR using 2-DG impairs the suppressive function of Treg and reduces Foxp3 expression level in human Treg (31). Deletion of mTORC1 in Tregs leads to severe inflammatory disease, reduced mitochondrial fitness, and impaired metabolic reprogramming (32). These findings underscore that glycolysis can support Treg proliferation but may compromise suppressive function unless carefully balanced by other pathways.
OXPHOS and lipid metabolism in Treg homeostasis
Beyond glycolysis, Tregs rely heavily on mitochondrial metabolism (Figure 1C). Deficiency in respiratory chain complex III within Treg cells leads to the accumulation of succinate and 2-hydroxyglutarate (2-HG) (33). These metabolites competitively inhibit TET enzymes by displacing their cofactor, α-ketoglutarate, causing hypermethylation and subsequent silencing of key immunosuppressive genes like PD-1, CD73, and TIGIT (34, 35). Ultimately, this epigenetic silencing impairs the cell’s ability to produce critical co-inhibitory molecules and ectoenzymes, severely decreasing the Treg’s immunosuppressive function. Foxp3 itself directly links transcriptional programming to mitochondrial metabolism. By promoting OXPHOS and FAO, Foxp3 enhances spare respiratory capacity and prevents fatty acid-induced apoptosis. Inhibition of fatty acid binding protein 5 (FABP5) disrupts mitochondrial integrity, reduces OXPHOS, and skews Treg metabolism toward glycolysis, compromising their suppressive function (36).
Liver kinase B1 (LKB1), also known as STK11, is a key metabolic sensor in Tregs. LKB1 deficiency leads to reduced mitochondrial oxygen consumption, ATP production, and mitochondrial mass, resulting in impaired Treg survival and function both in vitro and in vivo (37, 38). Metabolomic profiling shows that TCA cycle intermediates and fatty acid oxidation (FAO) products are markedly reduced upon LKB1 deletion (39). LKB1 also regulates cholesterol biosynthesis via the mevalonate pathway. Tregs lacking LKB1 or the key enzyme HMGCR show impaired lipid metabolism, increased inflammatory cytokine production, and systemic autoimmunity, which can be partially rescued by mevalonate supplementation (38). These results emphasize that lipid metabolism is not only a source of bioenergetics but also provides critical intermediates for maintaining immune tolerance. CD36, a fatty acid transporter, has been identified as another important metabolic adaptation in intratumoral Tregs. By facilitating uptake of long-chain fatty acids and oxidized lipoproteins, CD36 enhances PPAR-β signaling, mitochondrial fitness, and NAD+/NADH balance, thereby promoting Tregs survival in nutrient-poor tumor microenvironments (40). Together, these findings demonstrate that Tregs require intact mitochondrial and lipid metabolic pathways for long-term survival, stability, and function.
Metabolic crosstalk with the microenvironment
Treg metabolism is highly sensitive to external cues. Nutrient availability, oxygen tension, and microbial metabolites all shape Tregs function. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate produced by gut microbiota, promote Tregs differentiation via epigenetic regulation of Foxp3 and enhanced FAO (26). Propionate facilitates Treg differentiation in vitro via the GPR43-HDAC6 axis, which correlates with an elevated Treg/Th17 ratio in vivo in mice (41). Similarly, butyrate and its derivatives exert potent pro-regulatory effects. Treatment with methyl butyrate fosters Treg development and IL-10 secretion in the draining lymph nodes of EAE mice and also directly promotes Treg differentiation in vitro (42). Furthermore, evidence indicates that butyrate itself helps regulate the Th17/Treg balance by activating PPARγ, a process which subsequently promotes the upregulation of CD36 and Foxp3 in vitro (43) (Figure 1C). Tryptophan metabolites, generated by commensals through the indoleamine-2,3-dioxygenase (IDO) pathway, also favor Treg stability while suppressing effector T cell responses. These findings highlight that Treg metabolism is not cell-autonomous but is deeply influenced by interactions with the microbiome and tissue-specific niches. Such insights raise the possibility that microbiome-targeted therapies could modulate Treg metabolism to treat inflammatory diseases.
Treg metabolism in disease
Autoimmunity and chronic inflammation
Metabolic dysregulation of Tregs contributes to autoimmune pathology (Figures 2A–C). For example, constitutive Glut1 activation in Tregs reduces Foxp3 expression and impairs suppression in colitis models (27), whereas Glut1 deletion has little effect on Treg function (24). Obesity is associated with increased mTOR activation, glycolytic gene expression, and reduced Treg frequency in adipose tissue, contributing to insulin resistance and chronic inflammation (44). In multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), Tregs display impaired mitochondrial metabolism, reduced spare respiratory capacity, and altered lipid handling, correlating with disease severity. Importantly, evidence from human studies highlights a distinct role for glycolysis in maintaining Treg stability. De Rosa et al. demonstrated that glycolysis controls the induction of human Tregs by modulating FOXP3 exon 2 splicing variants (45). Impaired glycolysis and reduced Foxp3 exon 2 (Foxp3-E2) expression were also observed in iTregs from patients with relapsing-remitting multiple sclerosis (RRMS) and type 1 diabetes (T1D) (45). Studies have shown that an increase of metabolic sensors such as HIF-1α is responsible for Th17/Treg imbalance that causes disease pathogenesis in EAE (46). Finally, mice models with Treg-specific deletion of LKB1 further demonstrating the relationship between metabolic dysregulation in Treg, Treg stability, and function in inducing immune imbalance (47). These observations underscore the potential of targeting Treg metabolism to restore tolerance in autoimmunity.
Figure 2. Treg metabolic changes in the context of disease. (A) Tumor infiltrating Tregs (TI-Tregs) have several adaptations: TI Tregs upregulate MCT1 for lactate uptake and Lactate dehydrogenase (LDh) for conversion of Lactate to pyruvate. Additionally, lactate derived PEP fuels TI-Treg proliferation. TI-Tregs upregulate Glut1 and Gult3 for glucose uptake and entry to OXPHOS. Hypoxic conditions induce HIF-1α upregulation and potential destabilization of Foxp3 causing TH17 skewing limiting suppressive function although this requires further studies. CD26 mediated LCFA uptake increases fatty acid oxidation and PPARγ signaling further supporting mitochondrial fitness and OXPHOS. TI-Tregs upregulate SCAP mediated SREBP activation to induce Fatty acid synthesis. Tregs achieve reduction of ROS associated with lipid metabolism by serine dependent glutathione (GSH) synthesis. (B) In high-fat diet induced colitis, Tregs uptake long chain fatty acids through CD36 leading to increased peroxide unsaturated fatty acid induced ferroptosis. In Multiple sclerosis, autoimmune hepatitis and type-1 diabetes, increased Akt phosphorylation and mTOR signaling induce expression of HIF-1α and Myc which results GLUT1 receptor and hexokinase 2 upregulation to facilitate glycolytic reprograming. Akt phosphorylation also induces FOXO further exacerbating IFNγ production. Reduced SCFA exacerbates Th17/Treg skewing in diseases such as IBD. Reduced LKB1 promotes reduced metabolic fitness and OXPHOS related gene expression as well as Foxp3 stability leading to autoimmune disorder such as acute graft-versus-host disease (aGVHD). (C) In Viral infection, Tregs upregulate Glut 1, and glycolytic genes HIF-1α and Myc while decreasing genes associated with. PPARγ signaling and FAO although additional studies are required to in this realm.
Cancer
In the tumor microenvironment (TME), Tregs adapt their metabolism to survive under hypoxic and nutrient-poor conditions (Figures 2A, B). Unlike effector T cells, which suffer from nutrient competition and exhaustion, mouse Tumor-infiltrating Tregs (TI-Tregs) upregulate lactate transporters (MCT1) and lactate dehydrogenase (LDh) to metabolize extracellular lactate into pyruvate for OXPHOS (48). Additionally, TI-Tregs also utilize Lactate to generate Phosphoenolpyruvate (PEP), a precursor of pyruvate suggesting increased gluconeogenesis to fuel their proliferation (48). Interestingly, mouse TI-Tregs upregulate HIF-1α due to hypoxic conditions, which enhances their glycolytic-driven migration but compromises their suppressive function (49, 50). To maintain suppressive function, mouse TI-Tregs utilize fatty acid and lipid metabolism; indeed, TI-Tregs upregulate CD36 expression, which enhances fatty acid oxidation and the PPAR signaling pathway responsible for mitochondrial fitness and adaptation to lipid metabolism (40). In humans, TI-Tregs also displayed a gene signature oriented to glycolysis and lipid biosynthesis (51). Additionally, mouse studies also show that TI-Tregs upregulate SCAP/SREBP signaling, leading to de novo lipid biosynthesis, including fatty acids and cholesterols (52, 53). To withstand the inevitable ROS build-up associated with increased lipid metabolism, TI-Tregs upregulate antioxidant molecule synthesis such as serine-dependent glutathione (GSH) synthesis (50, 54). This mechanism is conserved in humans, as pharmacological inhibition of GSH synthesis in human iTregs led to loss of suppression and reduced FoxP3 expression (54). Furthermore, TI-Tregs compete with effector T cell to uptake the limited glucose in the TME by upregulating GLUT1 and GLUT3 receptors (50). These adaptations allow them to maintain suppressive capacity and dampen anti-tumor immunity, representing a major barrier to immunotherapy. Lipid metabolism also plays a role in TI-Tregs; TI-Tregs display a metabolic preference for lipid utilization compared to their circulating counterparts in different types of human cancer. Functional studies also confirm that TI-Tregs uptake more fatty acids in mouse cancer models (40). Targeting Treg metabolism, for example, through inhibition of CD36 or MCT1, is therefore being explored as a strategy to selectively impair tumor-infiltrating Tregs while sparing systemic tolerance.
Infectious disease
In chronic viral infections such as HIV and HCV, Tregs expand and display altered metabolic signatures, contributing to viral persistence by suppressing effector T cell responses (Figure 2C). In chronic HIV patients undergoing AntiRetroviral Therapy (ART), a study revealed that gut Treg cells from patients had upregulated glycolysis-related genes while downregulating genes associated with OXPHOS and FAO, leading to Treg cells expansion with decreased function (55). A study on Tregs of Long-term non-progressor (LTNPs), a small group of HIV-infected individuals with decreased viral load without ART, has increased glycolytic genes such as Myc and HIF-1α and glycolytic receptors such as Glut1, while having decreased FAO and PPAR signaling, which suggests increased expansion but decreased Treg suppressive capacity (56). Conversely, in acute infection, Tregs may prevent immunopathology by limiting excessive inflammation (57). Yet, there is a large gap in knowledge regarding establishing a direct relationship between alteration of Treg metabolism under chronic and acute infections. Such investigations can provide bases for strategic manipulation of Treg metabolism to balance pathogen clearance with tissue protection.
Future directions and therapeutic implications
The field of Treg metabolism is rapidly evolving, with several promising directions. Therapeutic modulation of key metabolic pathways, such as mTOR, AMPK, and FAO, offers the potential to enhance or suppress Treg function depending on the disease context; for instance, metformin, an AMPK activator, promotes FAO and supports Treg survival in autoimmune settings. However, systemic manipulation of metabolism poses risks due to widespread effects, highlighting the need for precision targeting strategies that are tissue-specific or context-dependent. Ultimately, these insights hold strong potential for clinical translation, informing the design of adoptive Treg therapies for autoimmunity and transplantation, as well as strategies for selectively targeting Tregs to improve cancer immunotherapy.
Conclusion
Regulatory T cells are indispensable for immune tolerance and tissue homeostasis. Their ability to adapt metabolism between glycolysis, OXPHOS, and lipid pathways underlies their functional heterogeneity across contexts such as the thymus, peripheral tissues, and tumors. Dysregulated metabolism compromises their suppressive function and contributes to pathology in autoimmunity, cancer, chronic infection, and obesity. A deeper mechanistic understanding of Treg metabolism, combined with advances in technology, is likely to open new avenues for therapeutic intervention. Targeting metabolic pathways offers both opportunities and challenges but holds great promise for fine-tuning immune responses in diverse disease settings.
Author contributions
FG: Writing – original draft, Writing – review & editing. JH: Writing – original draft, Writing – review & editing. MB: Conceptualization, Funding acquisition, Supervision, Validation, Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
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.
References
1. Georgiev P, Benamar M, Han S, Haigis MC, Sharpe AH, and Chatila TA. Regulatory T cells in dominant immunologic tolerance. J Allergy Clin Immunol. (2024) 153:28–41. doi: 10.1016/j.jaci.2023.09.025
2. Oktelik FB, Luo Y, Benamar M, and Chatila TA. Inborn errors of regulatory T-cell differentiation and function. J Allergy Clin Immunol. (2025) 156. doi: 10.1016/j.jaci.2025.07.001
3. Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, and Ohkura N. Regulatory T cells and human disease. Annu Rev Immunol. (2020) 38:541–66. doi: 10.1146/annurev-immunol-042718-041717
4. Benamar M, Contini P, Schmitz-Abe K, Lanzetta O, Getachew F, Bachelin C, et al. Notch3 destabilizes regulatory T cells to drive autoimmune neuroinflammation in multiple sclerosis. Immunity. (2025) 58:2753–2768 e6. doi: 10.1016/j.immuni.2025.09.007
5. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. (2001) 27:68–73. doi: 10.1038/83784
6. Benamar M, Chen Q, Martinez-Blanco M, and Chatila TA. Regulatory T cells in allergic inflammation. Semin Immunol. (2023) 70:101847. doi: 10.1016/j.smim.2023.101847
7. Vignali DA, Collison LW, and Workman CJ. How regulatory T cells work. Nat Rev Immunol. (2008) 8:523–32. doi: 10.1038/nri2343
8. Savage TM, Fortson KT, De Los Santos-Alexis K, Oliveras-Alsina A, Rouanne M, Rae SS, et al. Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis. Immunity. (2024) 57:303–318 e6. doi: 10.1016/j.immuni.2024.01.009
9. Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, Yuan S, et al. A distinct function of regulatory T cells in tissue protection. Cell. (2015) 162:1078–89. doi: 10.1016/j.cell.2015.08.021
10. Harb H, Benamar M, Lai PS, Contini P, Griffith JW, Crestani E, et al. Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections. Immunity. (2021) 54:1186–1199 e7. doi: 10.1016/j.immuni.2021.04.002
11. Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, et al. A special population of regulatory T cells potentiates muscle repair. Cell. (2013) 155:1282–95. doi: 10.1016/j.cell.2013.10.054
12. Kong G, Xiong W, Li C, Xiao C, Wang S, Li W, et al. Treg cells-derived exosomes promote blood-spinal cord barrier repair and motor function recovery after spinal cord injury by delivering miR-2861. J Nanobiotechnol. (2023) 21:364. doi: 10.1186/s12951-023-02089-6
13. Wang G, Munoz-Rojas AR, Spallanzani RG, Franklin RA, Benoist C, and Mathis D. Adipose-tissue Treg cells restrain differentiation of stromal adipocyte precursors to promote insulin sensitivity and metabolic homeostasis. Immunity. (2024) 57:1345–1359 e5. doi: 10.1016/j.immuni.2024.04.002
14. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. (2001) 27:20–1. doi: 10.1038/83713
15. Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest. (2000) 106:R75–81. doi: 10.1172/JCI11679
16. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. (2001) 27:18–20. doi: 10.1038/83707
17. Charbonnier LM, Cui Y, Stephen-Victor E, Harb H, Lopez D, Bleesing JJ, et al. Functional reprogramming of regulatory T cells in the absence of Foxp3. Nat Immunol. (2019) 20:1208–19. doi: 10.1038/s41590-019-0442-x
18. Zemmour D, Charbonnier LM, Leon J, Six E, Keles S, Delville M, et al. Single-cell analysis of FOXP3 deficiencies in humans and mice unmasks intrinsic and extrinsic CD4(+) T cell perturbations. Nat Immunol. (2021) 22:607–19. doi: 10.1038/s41590-021-00910-8
19. de Candia P, Procaccini C, Russo C, Lepore MT, and Matarese G. Regulatory T cells as metabolic sensors. Immunity. (2022) 55:1981–92. doi: 10.1016/j.immuni.2022.10.006
20. Gerriets VA and Rathmell JC. Metabolic pathways in T cell fate and function. Trends Immunol. (2012) 33:168–73. doi: 10.1016/j.it.2012.01.010
21. van der Veeken J, Campbell C, Pritykin Y, Schizas M, Verter J, Hu W, et al. Genetic tracing reveals transcription factor Foxp3-dependent and Foxp3-independent functionality of peripherally induced Treg cells. Immunity. (2022) 55:1173–1184 e7. doi: 10.1016/j.immuni.2022.05.010
22. Schmitt EG and Williams CB. Generation and function of induced regulatory T cells. Front Immunol. (2013) 4:152. doi: 10.3389/fimmu.2013.00152
23. Priyadharshini B, Loschi M, Newton RH, Zhang JW, Finn KK, Gerriets VA, et al. Cutting edge: TGF-beta and phosphatidylinositol 3-kinase signals modulate distinct metabolism of regulatory T cell subsets. J Immunol. (2018) 201:2215–9. doi: 10.4049/jimmunol.1800311
24. Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. (2014) 20:61–72. doi: 10.1016/j.cmet.2014.05.004
25. Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol. (2012) 12:325–38. doi: 10.1038/nri3198
26. Kempkes RWM, Joosten I, Koenen H, and He X. Metabolic pathways involved in regulatory T cell functionality. Front Immunol. (2019) 10:2839. doi: 10.3389/fimmu.2019.02839
27. Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ, Nichols AG, et al. Foxp3 and Toll-like receptor signaling balance T(reg) cell anabolic metabolism for suppression. Nat Immunol. (2016) 17:1459–66. doi: 10.1038/ni.3577
28. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. (2011) 208:1367–76. doi: 10.1084/jem.20110278
29. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. (2009) 30:832–44. doi: 10.1016/j.immuni.2009.04.014
30. Chapman NM, Zeng H, Nguyen TM, Wang Y, Vogel P, Dhungana Y, et al. mTOR coordinates transcriptional programs and mitochondrial metabolism of activated T(reg) subsets to protect tissue homeostasis. Nat Commun. (2018) 9:2095. doi: 10.1038/s41467-018-04392-5
31. Procaccini C, Carbone F, Di Silvestre D, Brambilla F, De Rosa V, Galgani M, et al. The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity. (2016) 44:406–21. doi: 10.1016/j.immuni.2016.01.028
32. Zeng H, Yang K, Cloer C, Neale G, Vogel P, and Chi H. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature. (2013) 499:485–90. doi: 10.1038/nature12297
33. Weinberg SE, Singer BD, Steinert EM, Martinez CA, Mehta MM, Martinez-Reyes I, et al. Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature. (2019) 565:495–9. doi: 10.1038/s41586-018-0846-z
34. Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. (2012) 26:1326–38. doi: 10.1101/gad.191056.112
35. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. (2011) 19:17–30. doi: 10.1016/j.ccr.2010.12.014
36. Field CS, Baixauli F, Kyle RL, Puleston DJ, Cameron AM, Sanin DE, et al. Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for treg suppressive function. Cell Metab. (2020) 31:422–437 e5. doi: 10.1016/j.cmet.2019.11.021
37. He N, Fan W, Henriquez B, Yu RT, Atkins AR, Liddle C, et al. Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci U.S.A. (2017) 114:12542–7. doi: 10.1073/pnas.1715363114
38. Timilshina M, You Z, Lacher SM, Acharya S, Jiang L, Kang Y, et al. Activation of mevalonate pathway via LKB1 is essential for stability of T(reg) cells. Cell Rep. (2019) 27:2948–2961 e7. doi: 10.1016/j.celrep.2019.05.020
39. Yang K, Blanco DB, Neale G, Vogel P, Avila J, Clish CB, et al. Homeostatic control of metabolic and functional fitness of T(reg) cells by LKB1 signalling. Nature. (2017) 548:602–6. doi: 10.1038/nature23665
40. Wang H, Franco F, Tsui YC, Xie X, Trefny MP, Zappasodi R, et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol. (2020) 21:298–308. doi: 10.1038/s41590-019-0589-5
41. Du HX, Yue SY, Niu D, Liu C, Zhang LG, Chen J, et al. Gut microflora modulates th17/treg cell differentiation in experimental autoimmune prostatitis via the short-chain fatty acid propionate. Front Immunol. (2022) 13:915218. doi: 10.3389/fimmu.2022.915218
42. Wang C, Yang J, Xie L, Saimaier K, Zhuang W, Han M, et al. Methyl butyrate alleviates experimental autoimmune encephalomyelitis and regulates the balance of effector T cells and regulatory T cells. Inflammation. (2022) 45:977–91. doi: 10.1007/s10753-021-01596-8
43. Zhang W, Cheng C, Han Q, Chen Y, Guo J, Wu Q, et al. Flos Abelmoschus manihot extract attenuates DSS-induced colitis by regulating gut microbiota and Th17/Treg balance. BioMed Pharmacother. (2019) 117:109162. doi: 10.1016/j.biopha.2019.109162
44. Zhang S, Zhong R, Tang S, Chen L, and Zhang H. Metabolic regulation of the Th17/Treg balance in inflammatory bowel disease. Pharmacol Res. (2024) 203:107184. doi: 10.1016/j.phrs.2024.107184
45. De Rosa V, Galgani M, Porcellini A, Colamatteo A, Santopaolo M, Zuchegna C, et al. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol. (2015) 16:1174–84. doi: 10.1038/ni.3269
46. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. (2011) 146:772–84. doi: 10.1016/j.cell.2011.07.033
47. Su X, Wang Q, Guo W, Pei X, Niu Q, Liu M, et al. Loss of Lkb1 impairs Treg function and stability to aggravate graft-versus-host disease after bone marrow transplantation. Cell Mol Immunol. (2020) 17:483–95. doi: 10.1038/s41423-019-0312-3
48. Watson MJ, Vignali PDA, Mullett SJ, Overacre-Delgoffe AE, Peralta RM, Grebinoski S, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. (2021) 591:645–51. doi: 10.1038/s41586-020-03045-2
49. Miska J, Lee-Chang C, Rashidi A, Muroski ME, Chang AL, Lopez-Rosas A, et al. HIF-1alpha is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep. (2019) 27:226–237 e4. doi: 10.1016/j.celrep.2019.03.029
50. Saravia J and Chi H. Immunometabolism of regulatory T cells in cancer. Oncogene. (2025) 44:2011–24. doi: 10.1038/s41388-025-03458-1
51. Pacella I, Procaccini C, Focaccetti C, Miacci S, Timperi E, Faicchia D, et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc Natl Acad Sci U.S.A. (2018) 115:E6546–55. doi: 10.1073/pnas.1720113115
52. Lim SA, Wei J, Nguyen TM, Shi H, Su W, Palacios G, et al. Lipid signalling enforces functional specialization of T(reg) cells in tumours. Nature. (2021) 591:306–11. doi: 10.1038/s41586-021-03235-6
53. Zhou Z, Xu J, Liu S, Lv Y, Zhang R, Zhou X, et al. Infiltrating treg reprogramming in the tumor immune microenvironment and its optimization for immunotherapy. biomark Res. (2024) 12:97. doi: 10.1186/s40364-024-00630-9
54. Kurniawan H, FranChina DG, Guerra L, Bonetti L, Baguet LS, Grusdat M, et al. Glutathione restricts serine metabolism to preserve regulatory T cell function. Cell Metab. (2020) 31:920–936 e7. doi: 10.1016/j.cmet.2020.03.004
55. Yu M, Qu M, Wang Z, Zhen C, Yang B, Zhang Y, et al. Dysfunction and metabolic reprogramming of gut regulatory T cells in HIV-infected immunological non-responders. Cells. (2025) 14. doi: 10.3390/cells14151164
56. Shahbaz S, Jovel J, and Elahi S. Differential transcriptional and functional properties of regulatory T cells in HIV-infected individuals on antiretroviral therapy and long-term non-progressors. Clin Transl Immunol. (2021) 10:e1289. doi: 10.1002/cti2.1289
Keywords: regulatory T cells, Foxp3, metabolism, immune tolerance, diseases
Citation: Getachew F, Hu J and Benamar M (2025) Metabolic regulation of regulatory T cells: mechanisms, heterogeneity, and implications in disease. Front. Immunol. 16:1729690. doi: 10.3389/fimmu.2025.1729690
Received: 21 October 2025; Accepted: 28 November 2025; Revised: 25 November 2025;
Published: 12 December 2025.
Edited by:
Qun Wang, Shandong University, ChinaReviewed by:
Yohei Sato, University of Fukui, JapanCopyright © 2025 Getachew, Hu and Benamar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mehdi Benamar, TWVoZGkuQmVuYW1hckBjaGlsZHJlbnMuaGFydmFyZC5lZHU=
†These authors have contributed equally to this work