Savage, P. A., Klawon, D. E. J. & Miller, C. H. Regulatory T cell improvement. Annu. Rev. Immunol. 38, 421–453 (2020).
Nishizuka, Y. & Sakakura, T. Thymus and replica: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166, 753–755 (1969).
Zhang, H. et al. Ldl cholesterol suppresses human iTreg differentiation and nTreg operate via mitochondria-related mechanisms. J. Transl. Med. 21, 224 (2023).
van der Veeken, J. et al. Genetic tracing reveals transcription issue Foxp3-dependent and Foxp3-independent performance of peripherally induced Treg cells. Immunity 55, 1173–1184.e1177 (2022).
Bluestone, J. A., McKenzie, B. S., Beilke, J. & Ramsdell, F. Alternatives for Treg cell remedy for the therapy of human illness. Entrance. Immunol. 14, 1166135 (2023).
Sakaguchi, S. et al. Regulatory T cells and human illness. Annu. Rev. Immunol. 38, 541–566 (2020).
Wing, Okay. et al. CTLA-4 management over Foxp3+ regulatory T cell operate. Science 322, 271–275 (2008).
Tekguc, M. et al. Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells. Proc. Natl. Acad. Sci. USA. 118, e2023739118 (2021).
Gertel, S., Polachek, A., Elkayam, O. & Furer, V. Lymphocyte activation gene-3 (LAG-3) regulatory T cells: an evolving biomarker for therapy response in autoimmune ailments. Autoimmun. Rev. 21, 103085 (2022).
Huang, C. T. et al. Function of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004).
Akkaya, B. et al. Regulatory T cells mediate particular suppression by depleting peptide-MHC class II from dendritic cells. Nat. Immunol. 20, 218–231 (2019).
Cao, X. et al. Granzyme B and perforin are necessary for regulatory T cell-mediated suppression of tumor clearance. Immunity 27, 635–646 (2007).
Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits irritation at environmental interfaces. Immunity 28, 546–558 (2008).
Collison, L. W. et al. IL-35-mediated induction of a potent regulatory T cell inhabitants. Nat. Immunol. 11, 1093–1101 (2010).
Timperi, E. & Barnaba, V. CD39 regulation and features in T cells. Int. J. Mol. Sci. 22, 8068 (2021).
Borsellino, G. et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110, 1225–1232 (2007).
Chinen, T. et al. An important function for the IL-2 receptor in T(reg) cell operate. Nat. Immunol. 17, 1322–1333 (2016).
Cusick, M. F., Libbey, J. E. & Fujinami, R. S. Molecular mimicry as a mechanism of autoimmune illness. Clin. Rev. Allergy Immunol. 42, 102–111 (2012).
Klawon, D. E. J. et al. Regulatory T cells constrain T cells of shared specificity to implement tolerance throughout an infection. Science 387, eadk3248 (2025).
Feuerer, M. et al. Lean, however not overweight, fats is enriched for a singular inhabitants of regulatory T cells that have an effect on metabolic parameters. Nat. Med. 15, 930–939 (2009).
Panduro, M., Benoist, C. & Mathis, D. Tissue Tregs. Annu. Rev. Immunol. 34, 609–633 (2016).
Burzyn, D. et al. A particular inhabitants of regulatory T cells potentiates muscle restore. Cell 155, 1282–1295 (2013).
Kuswanto, W. et al. Poor restore of skeletal muscle in growing older mice displays a defect in native, interleukin-33-dependent accumulation of regulatory T cells. Immunity 44, 355–367 (2016).
Shevach, E. M. & Thornton, A. M. tTregs, pTregs, and iTregs: similarities and variations. Immunol. Rev. 259, 88–102 (2014).
Sakaguchi, S., Takahashi, T. & Nishizuka, Y. Examine on mobile occasions in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes injury after adoptive switch. J. Exp. Med. 156, 1565–1576 (1982).
Sakaguchi, S. et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes numerous autoimmune ailments. J. Immunol. 155, 1151–1164 (1995).
Kim, C. H. FOXP3 and its function within the immune system. Adv. Exp. Med. Biol. 665, 17–29 (2009).
Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is attributable to mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).
Hori, S., Nomura, T. & Sakaguchi, S. Management of regulatory T cell improvement by the transcription issue Foxp3. Science 299, 1057–1061 (2003).
Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 packages the event and performance of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).
Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An important function for Scurfin in CD4+CD25+T regulatory cells. Nat. Immunol. 4, 337–342 (2003).
Williams, L. M. & Rudensky, A. Y. Upkeep of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat. Immunol. 8, 277–284 (2007).
Wang, J. et al. Human FOXP3 and tumour microenvironment. Immunology 168, 248–255 (2023).
Sumida, T. S., Cheru, N. T. & Hafler, D. A. The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune ailments. Nat. Rev. Immunol. 24, 503–517 (2024).
Toomer, Okay. H. et al. Important and non-overlapping IL-2Rα-dependent processes for thymic improvement and peripheral homeostasis of regulatory T cells. Nat. Commun. 10, 1037 (2019).
Dikiy, S. et al. A distal Foxp3 enhancer permits interleukin-2 dependent thymic Treg cell lineage dedication for strong immune tolerance. Immunity 54, 931–946.e911 (2021).
Kawakami, R. et al. Distinct Foxp3 enhancer parts coordinate improvement, upkeep, and performance of regulatory T cells. Immunity 54, 947–961.e948 (2021).
Tang, S. et al. A lncRNA Dleu2-encoded peptide relieves autoimmunity by facilitating Smad3-mediated Treg induction. EMBO Rep. 25, 1208–1232 (2024).
Schlenner, S. M. et al. Smad3 binding to the foxp3 enhancer is dispensable for the event of regulatory T cells except for the intestine. J. Exp. Med. 209, 1529–1535 (2012).
Kaminski, A. et al. Resident regulatory T cells replicate the immune historical past of particular person lymph nodes. Sci. Immunol. 8, eadj5789 (2023).
Liston, A., Dooley, J. & Yshii, L. Mind-resident regulatory T cells and their function in well being and illness. Immunol. Lett. 248, 26–30 (2022).
Ramanan, D. et al. Regulatory T cells within the face of the intestinal microbiota. Nat. Rev. Immunol. 23, 749–762 (2023).
Thornton, A. M. et al. Helios(+) and Helios(-) Treg subpopulations are phenotypically and functionally distinct and categorical dissimilar TCR repertoires. Eur. J. Immunol. 49, 398–412 (2019).
Campos-Mora, M. et al. Neuropilin-1 is current on Foxp3+ T regulatory cell-derived small extracellular vesicles and mediates immunity towards pores and skin transplantation. J. Extracell. Vesicles 11, e12237 (2022).
Yu, F. et al. Dynamic expression of transcription components T-bet and GATA-3 by regulatory T cells maintains immunotolerance. Nat. Immunol. 16, 197–206 (2015).
Zheng, Y. et al. Regulatory T-cell suppressor program co-opts transcription issue IRF4 to manage T(H)2 responses. Nature 458, 351–356 (2009).
Zeng, Q. et al. A singular inhabitants: adipose-resident regulatory T cells. Entrance. Immunol. 9, 2075 (2018).
Bapat, S. P. et al. Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature 528, 137–141 (2015).
Cipolletta, D. et al. PPAR-γ is a serious driver of the buildup and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012).
Dominguez-Villar, M., Baecher-Allan, C. M. & Hafler, D. A. Identification of T helper sort 1-like, Foxp3+ regulatory T cells in human autoimmune illness. Nat. Med. 17, 673–675 (2011).
Pesenacker, A. M. et al. CD161 defines the subset of FoxP3+ T cells able to producing proinflammatory cytokines. Blood 121, 2647–2658 (2013).
Floess, S. et al. Epigenetic management of the foxp3 locus in regulatory T cells. PLoS Biol. 5, e38 (2007).
Povoleri, G. A. M. et al. Human retinoic acid-regulated CD161(+) regulatory T cells assist wound restore in intestinal mucosa. Nat. Immunol. 19, 1403–1414 (2018).
Tang, X. et al. Phenotype, operate, and scientific significance of CD26+ and CD161+Tregs in splenic marginal zone lymphoma. Clin. Most cancers Res. 28, 4322–4335 (2022).
Neuwirth, T. et al. The polyamine-regulating enzyme SSAT1 impairs tissue regulatory T cell operate in power cutaneous irritation. Immunity 58, 632–647.e612 (2025).
Shan, F. et al. Therapeutic focusing on of regulatory T cells in most cancers. Developments Most cancers 8, 944–961 (2022).
Miyao, T. et al. Plasticity of Foxp3(+) T cells displays promiscuous Foxp3 expression in standard T cells however not reprogramming of regulatory T cells. Immunity 36, 262–275 (2012).
Wang, J. et al. Transient expression of FOXP3 in human activated nonregulatory CD4+T cells. Eur. J. Immunol. 37, 129–138 (2007).
Allan, S. E. et al. Activation-induced FOXP3 in human T effector cells doesn’t suppress proliferation or cytokine manufacturing. Int. Immunol. 19, 345–354 (2007).
Tran, D. Q., Ramsey, H. & Shevach, E. M. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is reworking progress factor-beta dependent however doesn’t confer a regulatory phenotype. Blood 110, 2983–2990 (2007).
Zemmour, D. et al. Single-cell evaluation of FOXP3 deficiencies in people and mice unmasks intrinsic and extrinsic CD4(+) T cell perturbations. Nat. Immunol. 22, 607–619 (2021).
Roncarolo, M. G. et al. The biology of T regulatory sort 1 cells and their therapeutic utility in immune-mediated ailments. Immunity 49, 1004–1019 (2018).
Gagliani, N. et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory sort 1 cells. Nat. Med. 19, 739–746 (2013).
Raverdeau, M. et al. Retinoic acid-induced autoantigen-specific sort 1 regulatory T cells suppress autoimmunity. EMBO Rep. 20, e47121 (2019).
Umeshappa, C. S. et al. Liver-specific T regulatory type-1 cells program native neutrophils to suppress hepatic autoimmunity by way of CRAMP. Cell Rep. 34, 108919 (2021).
Sultan, H. et al. Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress most cancers immunotherapy. Nature 632, 182–191 (2024).
Malek, T. R. & Castro, I. Interleukin-2 receptor signaling: on the interface between tolerance and immunity. Immunity 33, 153–165 (2010).
Ju, B. et al. The proportion and phenotypic modifications of CD4(+)CD25(-)Foxp3(+) T cells in sufferers with untreated rheumatoid arthritis. BMC Immunol. 23, 41 (2022).
Chen, X. & Oppenheim, J. J. Resolving the identification fantasy: key markers of useful CD4+FoxP3+ regulatory T cells. Int. Immunopharmacol. 11, 1489–1496 (2011).
Luo, S. et al. Foxp3(+)CD8(+) regulatory T cells: bona fide Tregs with cytotoxic operate. Developments Immunol. 46, 324–337 (2025).
Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive operate of human CD4+T reg cells. J. Exp. Med. 203, 1701–1711 (2006).
Kim, M. S. et al. A comparability on viability between CD4+T cells and CD4+CD25+CD127- regulatory T cells by excimer laser within the peripheral blood in vitro. Photodermatol. Photoimmunol. Photomed. 37, 247–249 (2021).
Walter, G. J. et al. Phenotypic, useful, and gene expression profiling of peripheral CD45RA+ and CD45RO+CD4+CD25+CD127(low) Treg cells in sufferers with power rheumatoid arthritis. Arthritis Rheumatol. 68, 103–116 (2016).
Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693–1700 (2006).
Nakagawa, H. et al. Instability of Helios-deficient Tregs is related to conversion to a T-effector phenotype and enhanced antitumor immunity. Proc. Natl. Acad. Sci. USA. 113, 6248–6253 (2016).
Lam, A. J., Uday, P., Gillies, J. Okay. & Levings, M. Okay. Helios is a marker, not a driver, of human Treg stability. Eur. J. Immunol. 52, 75–84 (2022).
Takatori, H. et al. Helios enhances Treg cell operate in cooperation with FoxP3. Arthritis Rheumatol. 67, 1491–1502 (2015).
Kim, H. J. et al. Secure inhibitory exercise of regulatory T cells requires the transcription issue Helios. Science 350, 334–339 (2015).
Piersiala, Okay. et al. Tumour-draining lymph nodes in head and neck most cancers are characterised by accumulation of CTLA-4 and PD-1 expressing Treg cells. Transl. Oncol. 23, 101469 (2022).
Ohkura, N. & Sakaguchi, S. Transcriptional and epigenetic foundation of Treg cell improvement and performance: its genetic anomalies or variations in autoimmune ailments. Cell Res. 30, 465–474 (2020).
Mitsuiki, N., Schwab, C. & Grimbacher, B. What did we be taught from CTLA-4 insufficiency on the human immune system? Immunol. Rev. 287, 33–49 (2019).
Diamantopoulos, N. et al. ICOS-expressing regulatory T cells affect the composition of antitumor CTL populations. J. Immunol. 213, 753–762 (2024).
Yan, F. et al. Prognostic and therapeutic potential of imbalance between PD-1+CD8 and ICOS+Treg cells in superior HBV-HCC. Most cancers Sci. 115, 2553–2564 (2024).
Li, D. Y. & Xiong, X. Z. ICOS(+) Tregs: a useful subset of Tregs in immune ailments. Entrance. Immunol. 11, 2104 (2020).
Jin, X. et al. Use of Tregs as a cell-based remedy by way of CD39 for benign prostate hyperplasia with irritation. J. Cell. Mol. Med. 24, 5082–5096 (2020).
Chen, C. et al. CD39(+) regulatory T cells attenuate lipopolysaccharide-induced acute lung damage by way of autophagy and the ERK/FOS pathway. Entrance. Immunol. 11, 602605 (2020).
He, J. et al. TNFR2-expressing CD4(+)Foxp3(+) regulatory T cells in most cancers immunology and immunotherapy. Prog. Mol. Biol. Transl. Sci. 164, 101–117 (2019).
Abi-Aad, S. J. et al. Simultaneous inhibition of PD-1 and LAG-3: the way forward for immunotherapy? Immunotherapy 15, 611–618 (2023).
Opstelten, R. et al. GPA33: a marker to determine steady human regulatory T cells. J. Immunol. 204, 3139–3148 (2020).
Zhao, Y. et al. Alterations in Helios+ T cell subsets in peripheral blood of early-stage lung adenocarcinoma sufferers: implications for early prognosis. Immunobiology 228, 152749 (2023).
Opstelten, R. et al. GPA33 is expressed on a number of human blood cell sorts and distinguishes CD4(+) central reminiscence T cells with and with out effector operate. Eur. J. Immunol. 51, 1377–1389 (2021).
Mensink, M. et al. TNFR2 costimulation differentially impacts regulatory and standard CD4(+) T-cell metabolism. Entrance. Immunol. 13, 881166 (2022).
Cantor, H. et al. Immunoregulatory circuits amongst T-cell units. II. Physiologic function of suggestions inhibition in vivo: absence in NZB mice. J. Exp. Med. 147, 1116–1125 (1978).
Jiang, H., Zhang, S. I. & Pernis, B. Function of CD8+T cells in murine experimental allergic encephalomyelitis. Science 256, 1213–1215 (1992).
Li, J. et al. KIR(+)CD8(+) T cells suppress pathogenic T cells and are energetic in autoimmune ailments and COVID-19. Science 376, eabi9591 (2022).
Churlaud, G. et al. Human and mouse CD8+CD25+FOXP3+ regulatory T cells at regular state and through interleukin-2 remedy. Entrance. Immunol. 6, 171 (2015).
Robb, R. J. et al. Identification and growth of extremely suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation. Blood 119, 5898–5908 (2012).
Joeris, T. et al. Intestinal cDC1 drive cross-tolerance to epithelial-derived antigen by way of induction of FoxP3+CD Tregs. Sci. Immunol. 6, eabd3774 (2021).
Vuttaradhi, V. Okay. et al. CD8+ regulatory T cells. Annu. Rev. Immunol. 44, 21–40 (2026).
Kim, H. J. et al. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is crucial for self tolerance. Nature 467, 328–332 (2010).
Kim, H. J. et al. CD8+T regulatory cells categorical the Ly49 Class I MHC receptor and are faulty in autoimmune susceptible B6-Yaa mice. Proc. Natl. Acad. Sci. USA. 108, 2010–2015 (2011).
Saligrama, N. et al. Opposing T cell responses in experimental autoimmune encephalomyelitis. Nature 572, 481–487 (2019).
Li, J. et al. Regulatory KIR(+)CD8(+) T cells are elevated throughout human being pregnant. Sci. Transl. Med. 17, eadm7697 (2025).
Chen, X. et al. Differential roles of human CD4(+) and CD8(+) regulatory T cells in controlling self-reactive immune responses. Nat. Immunol. 26, 230–239 (2025).
Niebel, D. et al. Cutaneous lupus erythematosus: an replace on pathogenesis and future therapeutic instructions. Am. J. Clin. Dermatol. 24, 521–540 (2023).
Lim, C. C. et al. Extreme infections in sufferers with lupus nephritis handled with immunosuppressants: a retrospective cohort examine. Nephrology 22, 478–484 (2017).
Fairfield, C. et al. Glucocorticosteroid-free versus glucocorticosteroid-containing immunosuppression for liver transplanted sufferers. Cochrane Database Syst. Rev. 4, Cd007606 (2018).
Mikami, N. et al. Producing functionally steady and antigen-specific T(reg) cells from effector T cells for cell remedy of inflammatory ailments. Sci. Transl. Med. 17, eadr6049 (2025).
Mukai, M. et al. Conversion of pathogenic T cells into functionally stabilized T(reg) cells for antigen-specific immunosuppression in pemphigus vulgaris. Sci. Transl. Med. 17, eadq9913 (2025).
Lio, C. W. & Hsieh, C. S. A two-step course of for thymic regulatory T cell improvement. Immunity 28, 100–111 (2008).
Klein, L., Kyewski, B., Allen, P. M. & Hogquist, Okay. A. Constructive and unfavourable number of the T cell repertoire: what thymocytes see (and don’t see). Nat. Rev. Immunol. 14, 377–391 (2014).
Aschenbrenner, Okay. et al. Number of Foxp3+ regulatory T cells particular for self antigen expressed and introduced by Aire+ medullary thymic epithelial cells. Nat. Immunol. 8, 351–358 (2007).
Leventhal, D. S. et al. Dendritic cells coordinate the event and homeostasis of organ-specific regulatory T cells. Immunity 44, 847–859 (2016).
Perry, J. S. A. et al. Distinct contributions of Aire and antigen-presenting-cell subsets to the era of self-tolerance within the thymus. Immunity 41, 414–426 (2014).
Li, M. O. & Rudensky, A. Y. T cell receptor signalling within the management of regulatory T cell differentiation and performance. Nat. Rev. Immunol. 16, 220–233 (2016).
Barnes, M. J. et al. Dedication to the regulatory T cell lineage requires CARMA1 within the thymus however not within the periphery. PLoS Biol. 7, e51 (2009).
Medoff, B. D. et al. Differential requirement for CARMA1 in agonist-selected T-cell improvement. Eur. J. Immunol. 39, 78–84 (2009).
Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression via its enhancer. Nat. Immunol. 9, 194–202 (2008).
Josefowicz, S. Z., Lu, L. F. & Rudensky, A. Y. Regulatory T cells: mechanisms of differentiation and performance. Annu. Rev. Immunol. 30, 531–564 (2012).
Tanaka, A. et al. Development of a T cell receptor signaling vary for spontaneous improvement of autoimmune illness. J. Exp. Med. 220, e20220386 (2023).
Sauer, S. et al. T cell receptor signaling controls Foxp3 expression by way of PI3K, Akt, and mTOR. Proc. Natl. Acad. Sci. USA. 105, 7797–7802 (2008).
Watanabe, M., Lu, Y., Breen, M. & Hodes, R. J. B7-CD28 co-stimulation modulates central tolerance by way of thymic clonal deletion and Treg era via distinct mechanisms. Nat. Commun. 11, 6264 (2020).
Tai, X., Cowan, M., Feigenbaum, L. & Singer, A. CD28 costimulation of creating thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat. Immunol. 6, 152–162 (2005).
Caramalho, I. et al. Human regulatory T-cell improvement is dictated by Interleukin-2 and -15 expressed in a non-overlapping sample within the thymus. J. Autoimmun. 56, 98–110 (2015).
Harris, F., Berdugo, Y. A. & Tree, T. IL-2-based approaches to Treg enhancement. Clin. Exp. Immunol. 211, 149–163 (2023).
Kumar, P. et al. Essential function of OX40 signaling within the TCR-independent part of human and murine thymic Treg era. Cell. Mol. Immunol. 16, 138–153 (2019).
Apert, C., Romagnoli, P. & van Meerwijk, J. P. M. IL-2 and IL-15 dependent thymic improvement of Foxp3-expressing regulatory T lymphocytes. Protein Cell 9, 322–332 (2018).
Apert, C. et al. IL-2 and IL-15 drive intrathymic improvement of distinct periphery-seeding CD4(+)Foxp3(+) regulatory T lymphocytes. Entrance. Immunol. 13, 965303 (2022).
Yoshie, O. & Matsushima, Okay. CCR4 and its ligands: from bench to bedside. Int. Immunol. 27, 11–20 (2015).
Thiault, N. et al. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the event of their precursors. Nat. Immunol. 16, 628–634 (2015).
Cowan, J. E., McCarthy, N. I. & Anderson, G. CCR7 controls thymus recirculation, however not manufacturing and emigration, of Foxp3(+) T cells. Cell Rep. 14, 1041–1048 (2016).
Nikolouli, E. et al. Recirculating IL-1R2(+) Tregs fine-tune intrathymic Treg improvement beneath inflammatory circumstances. Cell. Mol. Immunol. 18, 182–193 (2021).
Peters, V. A., Joesting, J. J. & Freund, G. G. IL-1 receptor 2 (IL-1R2) and its function in immune regulation. Mind Behav. Immun. 32, 1–8 (2013).
Wesa, A. & Galy, A. Elevated manufacturing of pro-inflammatory cytokines and enhanced T cell responses after activation of human dendritic cells with IL-1 and CD40 ligand. BMC Immunol. 3, 14 (2002).
Korn, T. et al. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of standard T cells into Foxp3+ regulatory T cells. Proc. Natl. Acad. Sci. USA. 105, 18460–18465 (2008).
Lemarquis, A. L. et al. Recirculating regulatory T cells mediate thymic regeneration via amphiregulin following injury. Immunity 58, 397–411.e396 (2025).
Levine, A. G., Arvey, A., Jin, W. & Rudensky, A. Y. Steady requirement for the TCR in regulatory T cell operate. Nat. Immunol. 15, 1070–1078 (2014).
Lathrop, S. Okay. et al. Peripheral training of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011).
Hsieh, C. S. et al. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat. Immunol. 7, 401–410 (2006).
Yeste, A. et al. Tolerogenic nanoparticles inhibit T cell–mediated autoimmunity via SOCS2. Sci. Sign. 9, ra61–ra61 (2016).
Krienke, C. et al. A noninflammatory mRNA vaccine for therapy of experimental autoimmune encephalomyelitis. Science 371, 145–153 (2021).
Scurlock, A. M. & Jones, S. M. An replace on immunotherapy for meals allergy. Curr. Opin. Allergy Clin. Immunol. 10, 587–593 (2010).
Lengthy, S. A. et al. Low-dose antigen promotes induction of FOXP3 in human CD4+T cells. J. Immunol. 187, 3511–3520 (2011).
Whibley, N., Tucci, A. & Powrie, F. Regulatory T cell adaptation within the gut and pores and skin. Nat. Immunol. 20, 386–396 (2019).
Kim, Okay. S. et al. Dietary antigens restrict mucosal immunity by inducing regulatory T cells within the small gut. Science 351, 858–863 (2016).
Syed, A. et al. Peanut oral immunotherapy leads to elevated antigen-induced regulatory T-cell operate and hypomethylation of forkhead field protein 3 (FOXP3). J. Allergy Clin. Immunol. 133, 500–510 (2014).
Vickery, B. P. et al. Sustained unresponsiveness to peanut in topics who’ve accomplished peanut oral immunotherapy. J. Allergy Clin. Immunol. 133, 468–475 (2014).
Takasato, Y. et al. Orally desensitized mast cells kind a regulatory community with Treg cells for the management of meals allergy. Mucosal Immunol. 14, 640–651 (2021).
Lozano-Ojalvo, D. et al. Allergen recognition by particular effector Th2 cells permits IL-2-dependent activation of regulatory T-cell responses in people. Allergy 78, 697–713 (2023).
Setoguchi, R., Hori, S., Takahashi, T. & Sakaguchi, S. Homeostatic upkeep of pure Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune illness by IL-2 neutralization. J. Exp. Med. 201, 723–735 (2005).
Liao, W., Lin, J. X. & Leonard, W. J. Interleukin-2 on the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38, 13–25 (2013).
Miyazaki, T. et al. Purposeful activation of Jak1 and Jak3 by selective affiliation with IL-2 receptor subunits. Science 266, 1045–1047 (1994).
Beadling, C. et al. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, however not the T cell antigen receptor, in human T lymphocytes. EMBO J. 13, 5605–5615 (1994).
Ross, S. H. & Cantrell, D. A. Signaling and performance of interleukin-2 in T lymphocytes. Annu. Rev. Immunol. 36, 411–433 (2018).
Solar, H. et al. IL-2 can sign by way of chemokine receptors to advertise regulatory T cells’ suppressive operate. Cell Rep. 42, 112996 (2023).
Setiady, Y. Y., Coccia, J. A. & Park, P. U. In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti-CD25 monoclonal antibody is mediated by FcgammaRIII+ phagocytes. Eur. J. Immunol. 40, 780–786 (2010).
Abbas, A. Okay. et al. Revisiting IL-2: biology and therapeutic prospects. Sci. Immunol. 3, eaat1482 (2018).
Arenas-Ramirez, N., Woytschak, J. & Boyman, O. Interleukin-2: biology, design and utility. Developments Immunol. 36, 763–777 (2015).
Trotta, E. et al. A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism. Nat. Med. 24, 1005–1014 (2018).
Yu, A. et al. Selective IL-2 responsiveness of regulatory T cells via a number of intrinsic mechanisms helps using low-dose IL-2 remedy in sort 1 diabetes. Diabetes 64, 2172–2183 (2015).
Tang, Q. et al. Central function of faulty interleukin-2 manufacturing within the triggering of islet autoimmune destruction. Immunity 28, 687–697 (2008).
Konrad, M. W. et al. Pharmacokinetics of recombinant interleukin 2 in people. Most cancers Res. 50, 2009–2017 (1990).
Service provider, R. et al. Tremendous-tuned long-acting interleukin-2 superkine potentiates sturdy immune responses in mice and non-human primate. J. Immunother. Most cancers 10, e003155 (2022).
Lengthy, S. A. et al. Rapamycin/IL-2 mixture remedy in sufferers with sort 1 diabetes augments Tregs but transiently impairs β-cell operate. Diabetes 61, 2340–2348 (2012).
Spangler, J. B. et al. Antibodies to interleukin-2 elicit selective T cell subset potentiation via distinct conformational mechanisms. Immunity 42, 815–825 (2015).
Pilat, N. et al. Treg-mediated extended survival of pores and skin allografts with out immunosuppression. Proc. Natl. Acad. Sci. USA. 116, 13508–13516 (2019).
Khoryati, L. et al. An IL-2 mutein engineered to advertise growth of regulatory T cells arrests ongoing autoimmunity in mice. Sci. Immunol. 5, eaba5264 (2020).
Music, Q. et al. Tolerogenic anti-IL-2 mAb prevents graft-versus-host illness whereas preserving robust graft-versus-leukemia exercise. Blood 137, 2243–2255 (2021).
VanDyke, D. et al. Engineered human cytokine/antibody fusion proteins develop regulatory T cells and confer autoimmune illness safety. Cell Rep. 41, 111478 (2022).
Peterson, L. B. et al. A protracted-lived IL-2 mutein that selectively prompts and expands regulatory T cells as a remedy for autoimmune illness. J. Autoimmun. 95, 1–14 (2018).
Ghelani, A. et al. Defining the edge IL-2 sign required for induction of selective Treg cell responses utilizing engineered IL-2 muteins. Entrance. Immunol. 11, 1106 (2020).
Jamison, B. L. et al. An IL-2 mutein will increase regulatory T cell suppression of dendritic cells by way of IL-10 and CTLA-4 to advertise T cell anergy. Cell Rep. 43, 114938 (2024).
Efe, O. et al. A humanized IL-2 mutein expands Tregs and prolongs transplant survival in preclinical fashions. J. Clin. Make investments. 134, e173107 (2024).
Li, M. O. et al. Reworking progress factor-beta regulation of immune responses. Annu. Rev. Immunol. 24, 99–146 (2006).
Wang, J., Zhao, X. & Wan, Y. Y. Intricacies of TGF-β signaling in Treg and Th17 cell biology. Cell. Mol. Immunol. 20, 1002–1022 (2023).
Marie, J. C., Letterio, J. J., Gavin, M. & Rudensky, A. Y. TGF-beta1 maintains suppressor operate and Foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 1061–1067 (2005).
Tang, N. et al. TGF-β inhibition by way of CRISPR promotes the long-term efficacy of CAR T cells towards strong tumors. JCI Perception 5, e133977 (2020).
Kanamori, M. et al. Induced regulatory T cells: their improvement, stability, and purposes. Developments Immunol. 37, 803–811 (2016).
Zheng, Y. et al. Function of conserved non-coding DNA parts within the Foxp3 gene in regulatory T-cell destiny. Nature 463, 808–812 (2010).
Ouyang, W., Beckett, O., Ma, Q. & Li, M. O. Reworking progress factor-beta signaling curbs thymic unfavourable choice selling regulatory T cell improvement. Immunity 32, 642–653 (2010).
Konkel, J. E. et al. Management of the event of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β. Nat. Immunol. 12, 312–319 (2011).
Fang, Y. et al. Mitochondrial fusion induced by reworking progress factor-β1 serves as a swap that governs the metabolic reprogramming throughout differentiation of regulatory T cells. Redox Biol. 62, 102709 (2023).
Koprivica, I. et al. Orally delivered all-trans-retinoic acid- and reworking progress factor-β-loaded microparticles ameliorate sort 1 diabetes in mice. Eur. J. Pharmacol. 864, 172721 (2019).
Elias, Okay. M. et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression via a Stat-3/Stat-5 unbiased signaling pathway. Blood 111, 1013–1020 (2008).
Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).
Chen, W. & Ten Dijke, P. Immunoregulation by members of the TGFβ superfamily. Nat. Rev. Immunol. 16, 723–740 (2016).
York, A. G. et al. IL-10 constrains sphingolipid metabolism to restrict irritation. Nature 627, 628–635 (2024).
Chaudhry, A. et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated irritation. Immunity 34, 566–578 (2011).
Shouval, D. S. et al. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti inflammatory macrophage operate. Immunity 40, 706–719 (2014).
Music, J. et al. MiR-192-5p/RB1/NF-κBp65 signaling axis promotes IL-10 secretion throughout gastric most cancers EMT to induce Treg cell differentiation within the tumour microenvironment. Clin. Transl. Med. 12, e992 (2022).
Laragione, T. et al. Magnesium will increase numbers of Foxp3+ Treg cells and reduces arthritis severity and joint injury in an IL-10-dependent method mediated by the intestinal microbiome. EBioMedicine 92, 104603 (2023).
Prodjinotho, U. F. et al. Helminthic dehydrogenase drives PGE(2) and IL-10 manufacturing in monocytes to potentiate Treg induction. EMBO Rep. 23, e54096 (2022).
Hsu, P. et al. IL-10 potentiates differentiation of human induced regulatory T cells by way of STAT3 and Foxo1. J. Immunol. 195, 3665–3674 (2015).
Ouyang, W. et al. Novel Foxo1-dependent transcriptional packages management T(reg) cell operate. Nature 491, 554–559 (2012).
Yang, X. et al. RNF213 promotes Treg cell differentiation by facilitating K63-linked ubiquitination and nuclear translocation of FOXO1. Nat. Commun. 15, 5961 (2024).
Ouyang, W. et al. Foxo proteins cooperatively management the differentiation of Foxp3+ regulatory T cells. Nat. Immunol. 11, 618–627 (2010).
Kerdiles, Y. M. et al. Foxo transcription components management regulatory T cell improvement and performance. Immunity 33, 890–904 (2010).
Collison, L. W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell operate. Nature 450, 566–569 (2007).
Collison, L. W. et al. The composition and signaling of the IL-35 receptor are unconventional. Nat. Immunol. 13, 290–299 (2012).
Shao, Y. et al. IL-35 promotes CD4+Foxp3+ Tregs and inhibits atherosclerosis by way of sustaining CCR5-amplified Treg-suppressive mechanisms. JCI Perception 6, e152511 (2021).
Rhodes, Okay. R. et al. Bioengineered particles develop myelin-specific regulatory T cells and reverse autoreactivity in a mouse mannequin of a number of sclerosis. Sci. Adv. 9, eadd8693 (2023).
Mikami, N. et al. Epigenetic conversion of standard T cells into regulatory T cells by CD28 sign deprivation. Proc. Natl. Acad. Sci. USA. 117, 12258–12268 (2020).
Ohkura, N. et al. T cell receptor stimulation-induced epigenetic modifications and Foxp3 expression are unbiased and complementary occasions required for Treg cell improvement. Immunity 37, 785–799 (2012).
Chi, H. Regulation and performance of mTOR signalling in T cell destiny selections. Nat. Rev. Immunol. 12, 325–338 (2012).
Yang, Okay. Regulation of Treg cell metabolism and performance in non-lymphoid tissues. Entrance. Immunol. 13, 909705 (2022).
Shi, L. Z. et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011).
Layman, A. A. Okay. et al. Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to forestall autoinflammatory illness. Nat. Commun. 8, 15677 (2017).
Park, Y. et al. TSC1 regulates the steadiness between effector and regulatory T cells. J. Clin. Make investments. 123, 5165–5178 (2013).
Shrestha, S. et al. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat. Immunol. 16, 178–187 (2015).
Powell, J. D., Pollizzi, Okay. N., Heikamp, E. B. & Horton, M. R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).
Merkenschlager, M. & von Boehmer, H. PI3 kinase signalling blocks Foxp3 expression by sequestering Foxo components. J. Exp. Med. 207, 1347–1350 (2010).
Procaccini, C. et al. An oscillatory swap in mTOR kinase exercise units regulatory T cell responsiveness. Immunity 33, 929–941 (2010).
Lee, J. H., Lydon, J. P. & Kim, C. H. Progesterone suppresses the mTOR pathway and promotes era of induced regulatory T cells with elevated stability. Eur. J. Immunol. 42, 2683–2696 (2012).
Newton, R., Priyadharshini, B. & Turka, L. A. Immunometabolism of regulatory T cells. Nat. Immunol. 17, 618–625 (2016).
Huynh, A. et al. Management of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat. Immunol. 16, 188–196 (2015).
Zeng, H. et al. mTORC1 {couples} immune alerts and metabolic programming to ascertain T(reg)-cell operate. Nature 499, 485–490 (2013).
Shackelford, D. B. & Shaw, R. J. The LKB1-AMPK pathway: metabolism and progress management in tumour suppression. Nat. Rev. Most cancers 9, 563–575 (2009).
Wu, D. et al. Lkb1 maintains T(reg) cell lineage identification. Nat. Commun. 8, 15876 (2017).
Campesato, L. F. et al. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine. Nat. Commun. 11, 4011 (2020).
Cheong, J. E. & Solar, L. Focusing on the IDO1/TDO2-KYN-AhR pathway for most cancers immunotherapy – challenges and alternatives. Developments Pharmacol. Sci. 39, 307–325 (2018).
Zhang, Q. et al. AhR activation promotes Treg cell era by enhancing Lkb1-mediated fatty acid oxidation by way of the Skp2/K63-ubiquitination pathway. Immunology 169, 412–430 (2023).
He, N. et al. Metabolic management of regulatory T cell (Treg) survival and performance by Lkb1. Proc. Natl. Acad. Sci. USA. 114, 12542–12547 (2017).
Wang, X. et al. Zfp335 establishes eTreg lineage and neonatal immune tolerance by focusing on Hadha-mediated fatty acid oxidation. J. Clin. Make investments. 133, e166628 (2023).
Timilshina, M. et al. Activation of mevalonate pathway by way of LKB1 is crucial for stability of T(reg) cells. Cell Rep. 27, 2948–2961.e2947 (2019).
Chen, Y., Zhang, J., Cui, W. & Silverstein, R. L. CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and destiny. J. Exp. Med. 219, e20211314 (2022).
Leduc, V., Jasmin-Bélanger, S. & Poirier, J. APOE and ldl cholesterol homeostasis in Alzheimer’s illness. Developments Mol. Med. 16, 469–477 (2010).
Chen, H. et al. Intestine microbial metabolites in inflammatory bowel illness: immunological mechanisms regulating Treg/Th17 steadiness and therapeutic potential. Entrance Immunol. 17, 1780865 (2026).
Brown, J. A. et al. Intestine microbiota promotes immune tolerance on the maternal-fetal interface. Cell 189, 196–214.e124 (2026).
Li, B. et al. Tryptophan catabolites from microbiota ameliorate immune-mediated hepatitis via activating aryl hydrocarbon receptor of T cells. Intestine Microbes 17, 2557979 (2025).
Yan, Y. et al. Metabolic profiles of regulatory T cells and their variations to the tumor microenvironment: implications for antitumor immunity. J. Hematol. Oncol. 15, 104 (2022).
Watson, M. J. et al. Metabolic assist of tumour-infiltrating regulatory T cells by lactic acid. Nature 591, 645–651 (2021).
Kumagai, S. et al. Lactic acid promotes PD-1 expression in regulatory T cells in extremely glycolytic tumor microenvironments. Most cancers Cell 40, 201–218.e209 (2022).
Tuomela, Okay. et al. Lactic acid improves Treg manufacturing and in vivo operate. Mol. Ther. Strategies Clin. Dev. 33, 101600 (2025).
Koenecke, C. et al. Alloantigen-specific de novo-induced Foxp3+ Treg revert in vivo and don’t shield from experimental GVHD. Eur. J. Immunol. 39, 3091–3096 (2009).
Li, J. et al. Management of Foxp3 induction and upkeep by sequential histone acetylation and DNA demethylation. Cell Rep. 37, 110124 (2021).
Polansky, J. Okay. et al. Methylation issues: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells. J. Mol. Med. 88, 1029–1040 (2010).
Iizuka-Koga, M. et al. Induction and upkeep of regulatory T cells by transcription components and epigenetic modifications. J. Autoimmun. 83, 113–121 (2017).
Vaeth, M. et al. Dependence on nuclear issue of activated T-cells (NFAT) ranges discriminates standard T cells from Foxp3+ regulatory T cells. Proc. Natl. Acad. Sci. USA. 109, 16258–16263 (2012).
Arroyo-Olarte, R. D. et al. Focused demethylation of FOXP3-TSDR enhances the suppressive capability of STAT6-deficient inducible T regulatory cells. Irritation 47, 2159–2172 (2024).
Yang, R. et al. Hydrogen sulfide promotes Tet1- and Tet2-mediated Foxp3 demethylation to drive regulatory T cell differentiation and keep immune homeostasis. Immunity 43, 251–263 (2015).
Kohli, R. M. & Zhang, Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502, 472–479 (2013).
Music, S. J. et al. MicroRNA-antagonism regulates breast most cancers stemness and metastasis by way of TET-family-dependent chromatin reworking. Cell 154, 311–324 (2013).
Yue, X. et al. Management of Foxp3 stability via modulation of TET exercise. J. Exp. Med. 213, 377–397 (2016).
Yue, X. et al. Entire-genome evaluation of TET dioxygenase operate in regulatory T cells. EMBO Rep. 22, e52716 (2021).
Wakamatsu, E. et al. Sturdy TCR stimulation promotes the stabilization of Foxp3 expression in regulatory T cells induced in vitro via growing the demethylation of Foxp3 CNS2. Biochem. Biophys. Res. Commun. 503, 2597–2602 (2018).
Takaki, H. et al. STAT6 Inhibits TGF-beta1-mediated Foxp3 induction via direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. J. Biol. Chem. 283, 14955–14962 (2008).
Arroyo-Olarte, R. D. et al. STAT6 controls the soundness and suppressive operate of regulatory T cells. Eur. J. Immunol. 53, e2250128 (2023).
Cameron, J., Martino, P., Nguyen, L. & Li, X. Innovative: CRISPR-based transcriptional regulators reveal transcription-dependent institution of epigenetic reminiscence of Foxp3 in regulatory T cells. J. Immunol. 205, 2953–2958 (2020).
Xiao, Y. et al. Histone acetyltransferase mediated regulation of FOXP3 acetylation and Treg operate. Curr. Opin. Immunol. 22, 583–591 (2010).
Haberland, M., Montgomery, R. L. & Olson, E. N. The various roles of histone deacetylases in improvement and physiology: implications for illness and remedy. Nat. Rev. Genet 10, 32–42 (2009).
Tao, R. et al. Deacetylase inhibition promotes the era and performance of regulatory T cells. Nat. Med. 13, 1299–1307 (2007).
Castillo, J. et al. CBP/p300 drives the differentiation of regulatory T cells via transcriptional and non-transcriptional mechanisms. Most cancers Res. 79, 3916–3927 (2019).
Chen, Q. et al. Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer brokers. Theranostics 12, 4935–4948 (2022).
Liu, Y. et al. Inhibition of p300 impairs Foxp3⁺ T regulatory cell operate and promotes antitumor immunity. Nat. Med. 19, 1173–1177 (2013).
Liu, Y. et al. Two histone/protein acetyltransferases, CBP and p300, are indispensable for Foxp3+ T-regulatory cell improvement and performance. Mol. Cell Biol. 34, 3993–4007 (2014).
Dong, Y., Yang, C. & Pan, F. Publish-translational laws of Foxp3 in Treg cells and their therapeutic purposes. Entrance. Immunol. 12, 626172 (2021).
Xu, L. et al. Constructive and unfavourable transcriptional regulation of the Foxp3 gene is mediated by entry and binding of the Smad3 protein to enhancer I. Immunity 33, 313–325 (2010).
Ma, Z. et al. Regulatory roles of intestinal CD4(+) T cells in irritation and their modulation by the intestinal microbiota. Intestine Microbes 17, 2560019 (2025).
Arpaia, N. et al. Metabolites produced by commensal micro organism promote peripheral regulatory T-cell era. Nature 504, 451–455 (2013).
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
Liu, L. et al. Microbiome-metabolome generated bile acids gatekeep infliximab efficacy in Crohn’s illness by licensing M1 suppression and Treg dominance. J. Adv. Res. 83, 789–806 (2026).
Cling, S. et al. Bile acid metabolites management TH17 and Treg cell differentiation. Nature 576, 143–148 (2019).
Li, W. et al. A bacterial bile acid metabolite modulates T(reg) exercise via the nuclear hormone receptor NR4A1. Cell Host Microbe 29, 1366–1377.e1369 (2021).
Kong, Y. et al. CAR-T cell remedy: developments, challenges and expanded purposes from most cancers to autoimmunity. Entrance. Immunol. 15, 1519671 (2024).
Sterner, R. C. & Sterner, R. M. CAR-T cell remedy: present limitations and potential methods. Blood Most cancers J. 11, 69 (2021).
Fritsche, E., Volk, H. D., Reinke, P. & Abou-El-Enein, M. Towards an optimized course of for scientific manufacturing of CAR-Treg cell remedy. Developments Biotechnol. 38, 1099–1112 (2020).
Barra, J. M. et al. Combinatorial genetic engineering technique for immune safety of stem cell-derived beta cells by chimeric antigen receptor regulatory T cells. Cell Rep. 43, 114994 (2024).
Muller, Y. D. et al. Precision engineering of an Anti-HLA-A2 chimeric antigen receptor in regulatory T cells for transplant immune tolerance. Entrance. Immunol. 12, 686439 (2021).
Eskandari, S. Okay., Daccache, A. & Azzi, J. R. Chimeric antigen receptor T(reg) remedy in transplantation. Developments Immunol. 45, 48–61 (2024).
MacDonald, Okay. G. et al. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J. Clin. Make investments. 126, 1413–1424 (2016).
Boardman, D. A. et al. Flagellin-specific human CAR Tregs for immune regulation in IBD. J. Autoimmun. 134, 102961 (2023).
Frikeche, J. et al. MOG-specific CAR Tregs: a novel method to deal with a number of sclerosis. J. Neuroinflammation 21, 268 (2024).
Spanier, J. A. et al. Tregs with an MHC class II peptide-specific chimeric antigen receptor forestall autoimmune diabetes in mice. J. Clin. Make investments. 133, e168601 (2023).
Arjomandnejad, M., Kopec, A. L. & Keeler, A. M. CAR-T regulatory (CAR-Treg) cells: engineering and purposes. Biomedicines 10, 287 (2022).
Fransson, M. et al. CAR/FoxP3-engineered T regulatory cells goal the CNS and suppress EAE upon intranasal supply. J. Neuroinflammation 9, 112 (2012).
Solar, N. et al. Nanoneedle-based electroporation for environment friendly manufacturing of human main chimeric antigen receptor regulatory T-cells. Adv. Sci. 12, e2416066 (2025).
Bacher, P. et al. Regulatory T cell specificity directs tolerance versus allergy towards aeroantigens in people. Cell 167, 1067–1078.e1016 (2016).
Boroughs, A. C. et al. Chimeric antigen receptor costimulation domains modulate human regulatory T cell operate. JCI Perception 5, e126194 (2019).
Lamarche, C. et al. Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion. Proc. Natl. Acad. Sci. USA. 120, e2219086120 (2023).
Lamarthée, B. et al. Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction. Nat. Commun. 12, 6446 (2021).
Doglio, M. et al. Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus. Nat. Commun. 15, 2542 (2024).
Cochrane, R. W. et al. Excessive-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells. Mol. Ther. Strategies Clin. Dev. 32, 101385 (2024).
Grauwet, Okay. et al. Stealth transgenes allow CAR-T cells to evade host immune responses. J. Immunother. Most cancers 12, e008417 (2024).
Wagner, D. L. et al. Immunogenicity of CAR T cells in most cancers remedy. Nat. Rev. Clin. Oncol. 18, 379–393 (2021).
Blat, D. et al. Suppression of murine colitis and its related most cancers by carcinoembryonic antigen-specific regulatory T cells. Mol. Ther. 22, 1018–1028 (2014).
Wendering, D. J. et al. The worth of a fast check of human regulatory T cell operate must be revised. Entrance. Immunol. 10, 150 (2019).
Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).
Göschl, L., Scheinecker, C. & Bonelli, M. Treg cells in autoimmunity: from identification to Treg-based therapies. Semin. Immunopathol. 41, 301–314 (2019).
Tanaka, A. & Sakaguchi, S. Focusing on Treg cells in most cancers immunotherapy. Eur. J. Immunol. 49, 1140–1146 (2019).
Hasenkrug, Okay. J., Chougnet, C. A. & Dittmer, U. Regulatory T cells in retroviral infections. PLoS Pathog. 14, e1006776 (2018).
Chi, X. et al. Innate and adaptive immune abnormalities underlying autoimmune ailments: the genetic connections. Sci. China Life Sci. 66, 1482–1517 (2023).
Grey, P. E. & David, C. Inborn errors of immunity and autoimmune illness. J. Allergy Clin. Immunol. Pract. 11, 1602–1622 (2023).
Torres-Aguilar, H., Sosa-Luis, S. A. & Aguilar-Ruiz, S. R. Infections as triggers of flares in systemic autoimmune ailments: novel innate immunity mechanisms. Curr. Opin. Rheumatol. 31, 525–531 (2019).
Cleaver, J. et al. The immunobiology of herpes simplex virus encephalitis and post-viral autoimmunity. Mind 147, 1130–1148 (2024).
Wagner, A. et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 184, 4168–4185.e4121 (2021).
Aso, Okay. et al. Itaconate ameliorates autoimmunity by modulating T cell imbalance by way of metabolic and epigenetic reprogramming. Nat. Commun. 14, 984 (2023).
Shakya, A. Okay. & Nandakumar, Okay. S. Antigen-specific tolerization and focused supply as therapeutic methods for autoimmune ailments. Developments Biotechnol. 36, 686–699 (2018).
Kiriakidou, M. & Ching, C. L. Systemic lupus erythematosus. Ann. Intern. Med. 172, Itc81–itc96 (2020).
Hoi, A., Igel, T., Mok, C. C. & Arnaud, L. Systemic lupus erythematosus. Lancet 403, 2326–2338 (2024).
Bluestone, J. A., Bour-Jordan, H., Cheng, M. & Anderson, M. T cells within the management of organ-specific autoimmunity. J. Clin. Make investments. 125, 2250–2260 (2015).
Huang, J. et al. Imbalance of Th17 cells, Treg cells and related cytokines in sufferers with systemic lupus erythematosus: a meta-analysis. Entrance. Immunol. 15, 1425847 (2024).
Bonelli, M., Smolen, J. S. & Scheinecker, C. Treg and lupus. Ann. Rheum. Dis. 69, i65–i66 (2010).
Dao, L. T. M. et al. Present cell therapies for systemic lupus erythematosus. Stem Cells Transl. Med. 13, 859–872 (2024).
Chuang, H. C. et al. BPI overexpression suppresses Treg differentiation and induces exosome-mediated irritation in systemic lupus erythematosus. Theranostics 11, 9953–9966 (2021).
Makita, S. et al. RNA-binding protein ZFP36L2 downregulates helios expression and suppresses the operate of regulatory T cells. Entrance. Immunol. 11, 1291 (2020).
von Spee-Mayer, C. et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in sufferers with systemic lupus erythematosus. Ann. Rheum. Dis. 75, 1407–1415 (2016).
Humrich, J. Y. et al. Low-dose interleukin-2 remedy in energetic systemic lupus erythematosus (LUPIL-2): a multicentre, double-blind, randomised and placebo-controlled part II trial. Ann. Rheum. Dis. 81, 1685–1694 (2022).
Raeber, M. E. et al. Interleukin-2 immunotherapy reveals human regulatory T cell subsets with distinct useful and tissue-homing traits. Immunity 57, 2232–2250.e2210 (2024).
Miao, M. et al. Therapeutic potential of focusing on Tfr/Tfh cell steadiness by low-dose-IL-2 in energetic SLE: a put up hoc evaluation from a double-blind RCT examine. Arthritis Res. Ther. 23, 167 (2021).
Humrich, J. Y. et al. Fast induction of scientific remission by low-dose interleukin-2 in a affected person with refractory SLE. Ann. Rheum. Dis. 74, 791–792 (2015).
Zhao, C. et al. Low dose of IL-2 mixed with rapamycin restores and maintains the long-term steadiness of Th17/Treg cells in refractory SLE sufferers. BMC Immunol. 20, 32 (2019).
Ilonen, J., Lempainen, J. & Veijola, R. The heterogeneous pathogenesis of sort 1 diabetes mellitus. Nat. Rev. Endocrinol. 15, 635–650 (2019).
Ben-Skowronek, I. et al. Potential therapeutic utility of regulatory T cells in diabetes mellitus sort 1. Int. J. Mol. Sci. 23, 390 (2021).
Liu, Y. F. et al. Immune and metabolic results of antigen-specific immunotherapy utilizing a number of β-cell peptides in sort 1. Diabetes Diabetes 71, 722–732 (2022).
Scherm, M. G. et al. miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in fashions of sort 1 diabetes. Nat. Commun. 10, 5697 (2019).
Serr, I. et al. Kind 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice. Nat. Commun. 7, 10991 (2016).
Bluestone, J. A. et al. Kind 1 diabetes immunotherapy utilizing polyclonal regulatory T cells. Sci. Transl. Med. 7, 315ra189 (2015).
Dong, S. et al. The impact of low-dose IL-2 and Treg adoptive cell remedy in sufferers with sort 1 diabetes. JCI Perception 6, e147474 (2021).
Marek-Trzonkowska, N. et al. Administration of CD4+CD25highCD127- regulatory T cells preserves β-cell operate in sort 1 diabetes in youngsters. Diabetes Care 35, 1817–1820 (2012).
Bender, C. et al. A part 2 randomized trial with autologous polyclonal expanded regulatory T cells in youngsters with new-onset sort 1 diabetes. Sci. Transl. Med. 16, eadn2404 (2024).
Uenishi, G. I. et al. GNTI-122: an autologous antigen-specific engineered Treg cell remedy for sort 1 diabetes. JCI Perception 9, e171844 (2024).
Venken, Okay., Hellings, N., Liblau, R. & Stinissen, P. Disturbed regulatory T cell homeostasis in a number of sclerosis. Developments Mol. Med. 16, 58–68 (2010).
Viglietta, V., Baecher-Allan, C., Weiner, H. L. & Hafler, D. A. Lack of useful suppression by CD4+CD25+ regulatory T cells in sufferers with a number of sclerosis. J. Exp. Med. 199, 971–979 (2004).
Dominguez-Villar, M. & Hafler, D. A. Regulatory T cells in autoimmune illness. Nat. Immunol. 19, 665–673 (2018).
Carbone, F. et al. Regulatory T cell proliferative potential is impaired in human autoimmune illness. Nat. Med. 20, 69–74 (2014).
Allan, S. E. et al. The function of two FOXP3 isoforms within the era of human CD4+ Tregs. J. Clin. Make investments. 115, 3276–3284 (2005).
Sumida, T. S. et al. An autoimmune transcriptional circuit drives FOXP3(+) regulatory T cell dysfunction. Sci. Transl. Med. 16, eadp1720 (2024).
Wang, X. et al. Immunoswitch nanomodulators allow energetic focusing on and selective proliferation of regulatory T cells for a number of sclerosis remedy. ACS Nano 18, 770–782 (2024).
Guo, Q. et al. Engineered PD-1/TIGIT dual-activating cell-membrane nanoparticles with dexamethasone act synergistically to form the effector T cell/Treg steadiness and alleviate systemic lupus erythematosus. Biomaterials 285, 121517 (2022).
Saadoun, D. et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 365, 2067–2077 (2011).
Chwojnicki, Okay. et al. Administration of CD4(+)CD25(excessive)CD127(-)FoxP3(+) regulatory T cells for relapsing-remitting a number of sclerosis: a part 1 examine. BioDrugs 35, 47–60 (2021).
Katsavos, S. & Coles, A. Alemtuzumab as therapy for a number of sclerosis. Chilly Spring Harb. Perspect. Med. 8, a032029 (2018).
Gilmore, W. et al. Repopulation of T, B, and NK cells following alemtuzumab therapy in relapsing-remitting a number of sclerosis. J. Neuroinflammation 17, 189 (2020).
Freedman, M. S., Kaplan, J. M. & Markovic-Plese, S. Insights into the mechanisms of the therapeutic efficacy of alemtuzumab in a number of sclerosis. J. Clin. Cell. Immunol. 4, 1000152 (2013).
Cox, A. L. et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in a number of sclerosis. Eur. J. Immunol. 35, 3332–3342 (2005).
De Mercanti, S. et al. Alemtuzumab long-term immunologic impact: Treg suppressor operate will increase as much as 24 months. Neurol. Neuroimmunol. Neuroinflamm. 3, e194 (2016).
Jones, J. L. & Coles, A. J. Mode of motion and scientific research with alemtuzumab. Exp. Neurol. 262 Pt A, 37–43 (2014).
Smolen, J. S., Aletaha, D. & McInnes, I. B. Rheumatoid arthritis. Lancet 388, 2023–2038 (2016).
Gravallese, E. M. & Firestein, G. S. Rheumatoid arthritis — frequent origins, divergent mechanisms. N. Engl. J. Med. 388, 529–542 (2023).
Smith, M. H. & Berman, J. R. What’s rheumatoid arthritis? JAMA 327, 1194 (2022).
Ishigaki, Okay. et al. HLA autoimmune danger alleles limit the hypervariable area of T cell receptors. Nat. Genet. 54, 393–402 (2022).
Bullock, J. et al. Rheumatoid arthritis: a short overview of the therapy. Med. Princ. Pract. 27, 501–507 (2018).
Ebringer, A. & Rashid, T. Rheumatoid arthritis is attributable to a Proteus urinary tract an infection. APMIS 122, 363–368 (2014).
Han, G. M., O’Neil-Andersen, N. J., Zurier, R. B. & Lawrence, D. A. CD4+CD25high T cell numbers are enriched within the peripheral blood of sufferers with rheumatoid arthritis. Cell. Immunol. 253, 92–101 (2008).
van Amelsfort, J. M. et al. CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: variations within the presence, phenotype, and performance between peripheral blood and synovial fluid. Arthritis Rheum. 50, 2775–2785 (2004).
Liu, M. F. et al. The presence of cytokine-suppressive CD4+CD25+T cells within the peripheral blood and synovial fluid of sufferers with rheumatoid arthritis. Scand. J. Immunol. 62, 312–317 (2005).
Möttönen, M. et al. CD4+CD25+T cells with the phenotypic and useful traits of regulatory T cells are enriched within the synovial fluid of sufferers with rheumatoid arthritis. Clin. Exp. Immunol. 140, 360–367 (2005).
Lina, C., Conghua, W., Nan, L. & Ping, Z. Mixed therapy of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in sufferers with rheumatoid arthritis. J. Clin. Immunol. 31, 596–605 (2011).
Kawashiri, S. Y. et al. CD4+CD25(excessive)CD127(low/-) Treg cell frequency from peripheral blood correlates with illness exercise in sufferers with rheumatoid arthritis. J. Rheumatol. 38, 2517–2521 (2011).
Kawashiri, S. Y. et al. CD4+CD25 highCD127 low/- Treg cell frequency from peripheral blood correlates with illness exercise in sufferers with rheumatoid arthritis. J. Rheumatol. 38, 2517–2521 (2011).
Moradi, B. et al. CD4⁺CD25⁺/highCD127low/⁻ regulatory T cells are enriched in rheumatoid arthritis and osteoarthritis joints-analysis of frequency and phenotype in synovial membrane, synovial fluid and peripheral blood. Arthritis Res. Ther. 16, R97 (2014).
Cao, D. et al. CD25brightCD4+ regulatory T cells are enriched in infected joints of sufferers with power rheumatic illness. Arthritis Res. Ther. 6, R335–R346 (2004).
Jiang, Q. et al. Perform and function of regulatory T cells in rheumatoid arthritis. Entrance. Immunol. 12, 626193 (2021).
Hashemi, V. et al. Polymorphism of Foxp3 gene impacts the frequency of regulatory T cells and illness exercise in sufferers with rheumatoid arthritis in Iranian inhabitants. Immunol. Lett. 204, 16–22 (2018).
Flores-Borja, F., Jury, E. C., Mauri, C. & Ehrenstein, M. R. Defects in CTLA-4 are related to irregular regulatory T cell operate in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA. 105, 19396–19401 (2008).
Solar, H. et al. Tim3(+) Foxp3 (+) Treg cells are potent inhibitors of effector T cells and are suppressed in rheumatoid arthritis. Irritation 40, 1342–1350 (2017).
Komatsu, N. et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62–68 (2014).
Zaiss, M. M. et al. Treg cells suppress osteoclast formation: a brand new hyperlink between the immune system and bone. Arthritis Rheum. 56, 4104–4112 (2007).
Wang, J. et al. Low-dose IL-2 improved scientific signs by restoring decreased regulatory T cells in sufferers with refractory rheumatoid arthritis: A randomized managed trial. Entrance. Immunol. 13, 947341 (2022).
Zhang, X. et al. Efficacy and security of low-dose interleukin-2 together with methotrexate in sufferers with energetic rheumatoid arthritis: a randomized, double-blind, placebo-controlled part 2 trial. Sign Transduct. Goal. Ther. 7, 67 (2022).
Tang, T. T. et al. Atorvastatin upregulates regulatory T cells and reduces scientific illness exercise in sufferers with rheumatoid arthritis. J. Lipid Res. 52, 1023–1032 (2011).
Zhang, S. X. et al. The efficacy and security of short-term and low-dose IL-2 mixed with tocilizumab to deal with rheumatoid arthritis. Entrance. Immunol. 15, 1359041 (2024).
Liu, Y. et al. Downregulation of N6-methyladenosine (m6A) methylation of Sema4D mRNA contributes to Treg dysfunction and allograft rejection. Am. J. Transplant. 25, 930–942 (2025).
Steven, P., Perez, V. L. & Sharma, A. Murine fashions of graft versus host illness (GVHD): concentrate on ocular GVHD. Ocul. Surf. 30, 179–186 (2023).
Meyer, E. H. et al. Donor regulatory T-cell remedy to forestall graft-versus-host illness. Blood 145, 2012–2024 (2025).
Zeiser, R. & Blazar, B. R. Acute graft-versus-host illness – biologic course of, prevention, and remedy. N. Engl. J. Med. 377, 2167–2179 (2017).
Gupta, P. Okay. et al. Decreased Satb1 expression predisposes CD4(+) T standard cells to Treg suppression and promotes transplant survival. Proc. Natl. Acad. Sci. USA. 119, e2205062119 (2022).
Gupta, P. Okay., McIntosh, C. M., Chong, A. S. & Alegre, M. L. The pursuit of transplantation tolerance: new mechanistic insights. Cell. Mol. Immunol. 16, 324–333 (2019).
Miller, M. L. et al. Spontaneous restoration of transplantation tolerance after acute rejection. Nat. Commun. 6, 7566 (2015).
Han, J. W. et al. Early discount of regulatory T cells is related to acute rejection in liver transplantation beneath tacrolimus-based immunosuppression with basiliximab induction. Am. J. Transplant. 20, 2058–2069 (2020).
Hu, M. et al. Infiltrating Foxp3(+) regulatory T cells from spontaneously tolerant kidney allografts reveal donor-specific tolerance. Am. J. Transplant. 13, 2819–2830 (2013).
Koreth, J. et al. Efficacy, sturdiness, and response predictors of low-dose interleukin-2 remedy for power graft-versus-host illness. Blood 128, 130–137 (2016).
Bader, C. S. et al. Single-center randomized trial of T-reg graft alone vs T-reg graft plus tacrolimus for the prevention of acute GVHD. Blood Adv. 8, 1105–1115 (2024).
Roemhild, A. et al. Regulatory T cells for minimising immune suppression in kidney transplantation: part I/IIa scientific trial. BMJ 371, m3734 (2020).
David, A. F. et al. Mixture cell remedy results in clonal deletion of donor-specific T cells in kidney transplant recipients. EBioMedicine 106, 105239 (2024).
Sánchez-Fueyo, A. et al. Applicability, security, and organic exercise of regulatory T cell remedy in liver transplantation. Am. J. Transpl. 20, 1125–1136 (2020).
Ravichandran, R. et al. Low-dose IL-2 prevents murine power cardiac allograft rejection: Function for IL-2-induced T regulatory cells and exosomes with PD-L1 and CD73. Am. J. Transplant. 22, 2180–2194 (2022).
Tahvildari, M. et al. In vivo growth of regulatory T cells by low-dose interleukin-2 therapy will increase allograft survival in corneal transplantation. Transplantation 100, 525–532 (2016).
Whitehouse, G. et al. IL-2 remedy restores regulatory T-cell dysfunction induced by calcineurin inhibitors. Proc. Natl. Acad. Sci. USA. 114, 7083–7088 (2017).
Webster, Okay. E. et al. In vivo growth of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts with out immunosuppression. J. Exp. Med. 206, 751–760 (2009).
Yamada, Y. et al. Biased IL-2 alerts induce Foxp3-rich pulmonary lymphoid buildings and facilitate long-term lung allograft acceptance in mice. Nat. Commun. 14, 1383 (2023).
Lim, T. Y. et al. Low dose interleukin-2 selectively expands circulating regulatory T cells however fails to advertise liver allograft tolerance in people. J. Hepatol. 78, 153–164 (2023).
Conrad, M. L. et al. Regulatory T cells and their function in allergic illness. Allergy 80, 77–93 (2024).
Lloyd, C. M. & Hessel, E. M. Features of T cells in bronchial asthma: extra than simply T(H)2 cells. Nat. Rev. Immunol. 10, 838–848 (2010).
Harb, H. et al. A regulatory T cell Notch4-GDF15 axis licenses tissue irritation in bronchial asthma. Nat. Immunol. 21, 1359–1370 (2020).
Aili, A. et al. LPG 18:0 is a basic biomarker of bronchial asthma and inhibits the differentiation and performance of regulatory T-cells. Eur. Respir. J. 64, 2301752 (2024).
Bates, J. T., Uematsu, S., Akira, S. & Mizel, S. B. Direct stimulation of tlr5+/+ CD11c+ cells is critical for the adjuvant exercise of flagellin. J. Immunol. 182, 7539–7547 (2009).
Shim, J. U. et al. Flagellin suppresses experimental bronchial asthma by producing regulatory dendritic cells and T cells. J. Allergy Clin. Immunol. 137, 426–435 (2016).
Wang, F. et al. A spleen-targeted tolerogenic mRNA-LNPs vaccine for the therapy of experimental bronchial asthma. Adv. Sci. 12, e2412543 (2025).
Shirai, T. et al. Celastrol suppresses humoral immune responses and autoimmunity by focusing on the COMMD3/8 advanced. Sci. Immunol. 8, eadc9324 (2023).
Ndeupen, S. et al. The mRNA-LNP platform’s lipid nanoparticle part utilized in preclinical vaccine research is very inflammatory. iScience 24, 103479 (2021).
Hibino, S. et al. Inhibition of Nr4a receptors enhances antitumor immunity by breaking Treg-mediated immune tolerance. Most cancers Res. 78, 3027–3040 (2018).
Tay, C., Tanaka, A. & Sakaguchi, S. Tumor-infiltrating regulatory T cells as targets of most cancers immunotherapy. Most cancers Cell 41, 450–465 (2023).
Arce Vargas, F. et al. Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors. Immunity 46, 577–586 (2017).
Ge, Z., Peppelenbosch, M. P., Sprengers, D. & Kwekkeboom, J. TIGIT, the following step in the direction of profitable mixture immune checkpoint remedy in most cancers. Entrance. Immunol. 12, 699895 (2021).
Sugiyama, D. et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in people. Proc. Natl. Acad. Sci. USA. 110, 17945–17950 (2013).
Kidani, Y. et al. CCR8-targeted particular depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting reminiscence. Proc. Natl. Acad. Sci. USA. 119, e2114282119 (2022).
Eschweiler, S. et al. Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs. Nature 605, 741–746 (2022).
Zhang, Y. et al. Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Most cancers Discov. 10, 422–439 (2020).
Becker, M. et al. Area of interest-specific management of tissue operate by regulatory T cells-Present challenges and views for focusing on metabolic illness. Cell Metab. 36, 229–239 (2024).
Zhao, X. Y. et al. The obesity-induced adipokine sST2 exacerbates adipose T(reg) and ILC2 depletion and promotes insulin resistance. Sci. Adv. 6, eaay6191 (2020).
Gilleron, J. et al. Rab4b deficiency in T cells promotes adipose Treg/Th17 imbalance, adipose tissue dysfunction, and insulin resistance. Cell Rep. 25, 3329–3341.e3325 (2018).
Wang, G. et al. Adipose-tissue Treg cells restrain differentiation of stromal adipocyte precursors to advertise insulin sensitivity and metabolic homeostasis. Immunity 57, 1345–1359.e1345 (2024).
Schmidleithner, L. et al. Enzymatic exercise of HPGD in Treg cells suppresses Tconv cells to take care of adipose tissue homeostasis and forestall metabolic dysfunction. Immunity 50, 1232–1248.e1214 (2019).
Wernstedt Asterholm, I. et al. Adipocyte irritation is crucial for wholesome adipose tissue growth and reworking. Cell Metab. 20, 103–118 (2014).
Nayer, B. et al. Native administration of regulatory T cells promotes tissue therapeutic. Nat. Commun. 15, 7863 (2024).
Fujisaki, J. et al. In vivo imaging of Treg cells offering immune privilege to the haematopoietic stem-cell area of interest. Nature 474, 216–219 (2011).
Li, J., Tan, J., Martino, M. M. & Lui, Okay. O. Regulatory T-cells: potential regulator of tissue restore and regeneration. Entrance. Immunol. 9, 585 (2018).
Loffredo, L. F., Savage, T. M., Ringham, O. R. & Arpaia, N. Treg-tissue cell interactions in restore and regeneration. J. Exp. Med. 221, e20231244 (2024).
Delacher, M. et al. Single-cell chromatin accessibility panorama identifies tissue restore program in human regulatory T cells. Immunity 54, 702–720.e717 (2021).
Delacher, M. et al. Precursors for nonlymphoid-tissue Treg cells reside in secondary lymphoid organs and are programmed by the transcription issue BATF. Immunity 52, 295–312.e211 (2020).
Delacher, M. et al. Rbpj expression in regulatory T cells is crucial for restraining T(H)2 responses. Nat. Commun. 10, 1621 (2019).
Delacher, M. et al. Genome-wide DNA-methylation panorama defines specialization of regulatory T cells in tissues. Nat. Immunol. 18, 1160–1172 (2017).
Vasanthakumar, A. et al. The transcriptional regulators IRF4, BATF and IL-33 orchestrate improvement and upkeep of adipose tissue-resident regulatory T cells. Nat. Immunol. 16, 276–285 (2015).
Schiering, C. et al. The alarmin IL-33 promotes regulatory T-cell operate within the gut. Nature 513, 564–568 (2014).
Chen, R. et al. Progranulin-dependent restore operate of regulatory T cells drives bone-fracture therapeutic. J. Clin. Make investments. 135, e180679 (2024).
Zhang, M. & Zhang, S. T cells in fibrosis and fibrotic ailments. Entrance. Immunol. 11, 1142 (2020).
Tang, T. T. et al. Regulatory T cells ameliorate cardiac reworking after myocardial infarction. Primary Res. Cardiol. 107, 232 (2012).
Alshoubaki, Y. Okay. et al. Tregs delivered post-myocardial infarction undertake an injury-specific phenotype selling cardiac restore by way of macrophages in mice. Nat. Commun. 15, 6480 (2024).
Kvakan, H. et al. Regulatory T cells ameliorate angiotensin II-induced cardiac injury. Circulation 119, 2904–2912 (2009).
Bansal, S. S. et al. Dysfunctional and proinflammatory regulatory T-lymphocytes are important for adversarial cardiac reworking in ischemic cardiomyopathy. Circulation 139, 206–221 (2019).
Lo Re, S. et al. Platelet-derived progress factor-producing CD4+ Foxp3+ regulatory T lymphocytes promote lung fibrosis. Am. J. Respir. Crit. Care Med. 184, 1270–1281 (2011).
Chen, J. et al. Glycyrrhetinic acid mitigates radiation-induced pulmonary fibrosis by way of inhibiting the secretion of TGF-β1 by Treg cells. Int. J. Radiat. Oncol. Biol. Phys. 118, 218–230 (2024).
Xiong, S. et al. Treg depletion attenuates irradiation-induced pulmonary fibrosis by decreasing fibrocyte accumulation, inducing Th17 response, and shifting IFN-γ, IL-12/IL-4, IL-5 steadiness. Immunobiology 220, 1284–1291 (2015).
Yan, S. et al. Low expression of lipoic acid synthase aggravates silica-induced pulmonary fibrosis by inhibiting the differentiation of Tregs in mice. Antioxid. Redox Sign 41, 216–232 (2024).
Liu, T. et al. Baicalin alleviates silica-induced lung irritation and fibrosis by inhibiting the Th17 response in C57BL/6 mice. J. Nat. Prod. 78, 3049–3057 (2015).
Frantz, C. et al. Driving function of interleukin-2-related regulatory CD4+T cell deficiency within the improvement of lung fibrosis and vascular reworking in a mouse mannequin of systemic sclerosis. Arthritis Rheumatol. 74, 1387–1398 (2022).
Ikeno, Y. et al. Foxp3+ regulatory T cells inhibit CCl(4)-induced liver irritation and fibrosis by regulating tissue mobile immunity. Entrance. Immunol. 11, 584048 (2020).
Savage, T. M. et al. Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis. Immunity 57, 303–318.e306 (2024).
Walker, M. D. & Shane, E. Postmenopausal osteoporosis. N. Engl. J. Med. 389, 1979–1991 (2023).
Bonnet, N. et al. RANKL inhibition improves muscle energy and insulin sensitivity and restores bone mass. J. Clin. Make investments. 129, 3214–3223 (2019).
Fischer, L. et al. Foxp3(+) Regulatory T Cells in Bone and Hematopoietic Homeostasis. Entrance. Endocrinol. 10, 578 (2019).
Shieh, A., Epeldegui, M., Karlamangla, A. S. & Greendale, G. A. Intestine permeability, irritation, and bone density throughout the menopause transition. JCI Perception 5, e134092 (2020).
Yang, X. et al. T cell-depleting nanoparticles ameliorate bone loss by decreasing activated T cells and regulating the Treg/Th17 steadiness. Bioact. Mater. 6, 3150–3163 (2021).
Luo, C. Y., Wang, L., Solar, C. & Li, D. J. Estrogen enhances the features of CD4(+)CD25(+)Foxp3(+) regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell. Mol. Immunol. 8, 50–58 (2011).
Guo, M. et al. Lactobacillus rhamnosus GG ameliorates osteoporosis in ovariectomized rats by regulating the Th17/Treg steadiness and intestine microbiota construction. Intestine Microbes 15, 2190304 (2023).
Dar, H. Y. et al. Lactobacillus acidophilus inhibits bone loss and will increase bone heterogeneity in osteoporotic mice by way of modulating Treg-Th17 cell steadiness. Bone Rep. 8, 46–56 (2018).
Hartemann, A. et al. Low-dose interleukin 2 in sufferers with sort 1 diabetes: a part 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 1, 295–305 (2013).
He, J. et al. Efficacy and security of low-dose IL-2 within the therapy of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis. 79, 141–149 (2020).
Saxena, V., Lakhan, R., Iyyathurai, J. & Bromberg, J. S. Mechanisms of exTreg induction. Eur. J. Immunol. 51, 1956–1967 (2021).
Lal, G. et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J. Immunol. 182, 259–273 (2009).
Skartsis, N. et al. IL-6 and TNFα drive in depth proliferation of human Tregs with out compromising their lineage stability or operate. Entrance. Immunol. 12, 783282 (2021).
Saigusa, R. et al. Single cell transcriptomics and TCR reconstruction reveal CD4 T cell response to MHC-II-restricted APOB epitope in human heart problems. Nat. Cardiovasc. Res. 1, 462–475 (2022).
Jiang, Z. et al. TMED4 facilitates regulatory T cell suppressive operate by way of ROS homeostasis in tumor and autoimmune mouse fashions. J. Clin. Make investments. 135, e179874 (2024).
Xu, Y. et al. The E3 ligase Hrd1 stabilizes Tregs by antagonizing inflammatory cytokine-induced ER stress response. JCI Perception 4, e121887 (2019).
Freuchet, A. et al. Identification of human exT(reg) cells as CD16(+)CD56(+) cytotoxic CD4(+) T cells. Nat. Immunol. 24, 1748–1761 (2023).
Alissafi, T. et al. Mitochondrial oxidative injury underlies regulatory T cell defects in autoimmunity. Cell Metab. 32, 591–604.e597 (2020).
Parashar, S. et al. ER stress induced mitochondrial dysfunction drives Treg instability in coronary artery illness. EMBO Mol. Med. 17, 3250–3274 (2025).
Arvey, A. et al. Genetic and epigenetic variation within the lineage specification of regulatory T cells. eLife 4, e07571 (2015).
Yadav, M. et al. Neuropilin-1 distinguishes pure and inducible regulatory T cells amongst regulatory T cell subsets in vivo. J. Exp. Med. 209, 1713–1722, s1711–1719 (2012).
Weiss, J. M. et al. Neuropilin 1 is expressed on thymus-derived pure regulatory T cells, however not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209, 1723–1742, s1721 (2012).
Thornton, A. M. et al. Expression of Helios, an Ikaros transcription issue member of the family, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433–3441 (2010).
Elkord, E. Helios shouldn’t be cited as a marker of human thymus-derived Tregs. Commentary: helios(+) and helios(-) cells coexist throughout the pure FOXP3(+) T regulatory cell subset in people. Entrance. Immunol. 7, 276 (2016).
Ziegler, S. F. FOXP3: of mice and males. Annu. Rev. Immunol. 24, 209–226 (2006).
Du, J. et al. FOXP3 exon 2 controls T(reg) stability and autoimmunity. Sci. Immunol. 7, eabo5407 (2022).
Miyara, M. & Sakaguchi, S. Human FoxP3(+)CD4(+) regulatory T cells: their knowns and unknowns. Immunol. Cell Biol. 89, 346–351 (2011).
Balcerek, J. et al. Polyclonal regulatory T cell manufacturing beneath cGMP: a decade of expertise. Entrance. Immunol. 12, 744763 (2021).
Brunstein, C. G. et al. Umbilical twine blood-derived T regulatory cells to forestall GVHD: kinetics, toxicity profile, and scientific impact. Blood 127, 1044–1051 (2016).
Obradovic, A. et al. Systematic elucidation and pharmacological focusing on of tumor-infiltrating regulatory T cell grasp regulators. Most cancers Cell 41, 933–949.e911 (2023).
Ramirez, R. N. et al. FoxP3 associates with enhancer-promoter loops to control T(reg)-specific gene expression. Sci. Immunol. 7, eabj9836 (2022).
Huang, R. et al. Plant exosomes fused with engineered mesenchymal stem cell-derived nanovesicles for synergistic remedy of autoimmune pores and skin problems. J. Extracell. Vesicles 12, e12361 (2023).
McHugh, M. D. et al. Paracrine co-delivery of TGF-β and IL-2 utilizing CD4-targeted nanoparticles for induction and upkeep of regulatory T cells. Biomaterials 59, 172–181 (2015).
Haist, M., Mailänder, V. & Bros, M. Nanodrugs focusing on T cells in tumor remedy. Entrance. Immunol. 13, 912594 (2022).
Ramanan, D. et al. Homeostatic, repertoire and transcriptional relationships between colon T regulatory cell subsets. Proc. Natl. Acad. Sci. USA. 120, e2311566120 (2023).
Dixon, M. L. et al. Reworking of the tumor microenvironment by way of disrupting Blimp1(+) effector Treg exercise augments response to anti-PD-1 blockade. Mol. Most cancers 20, 150 (2021).
Muñoz-Rojas, A. R. & Mathis, D. Tissue regulatory T cells: regulatory chameleons. Nat. Rev. Immunol. 21, 597–611 (2021).
Kalekar, L. A. et al. Regulatory T cells in pores and skin are uniquely poised to suppress profibrotic immune responses. Sci. Immunol. 4, eaaw2910 (2019).
Malhotra, N. et al. RORα-expressing T regulatory cells restrain allergic pores and skin irritation. Sci. Immunol. 3, eaao6923 (2018).
Min, H. Okay. et al. Protein inhibitor of activated STAT3 reduces peripheral arthritis and intestine irritation and regulates the Th17/Treg cell imbalance by way of STAT3 signaling in a mouse mannequin of spondyloarthritis. J. Transl. Med. 17, 18 (2019).
Asakawa, M. et al. A novel JAK-STAT inhibitor, 2-[(3-Carbamoyl-2-thienyl)amino]-2-oxoethyl(2,6-dichlorophenyl)acetate, suppresses helper T cell differentiation in vitro and collagen-induced arthritis in vivo. Biochem. Biophys. Res. Commun. 468, 766–773 (2015).
Strainic, M. G. et al. Absence of signaling into CD4⁺ cells by way of C3aR and C5aR permits autoinductive TGF-β1 signaling and induction of Foxp3⁺ regulatory T cells. Nat. Immunol. 14, 162–171 (2013).
Lim, S. M. et al. Neomangiferin modulates the Th17/Treg steadiness and ameliorates colitis in mice. Phytomedicine 23, 131–140 (2016).
Shen, Y. et al. Sorafenib promotes Treg cell differentiation to compromise its efficacy by way of VEGFR/AKT/Foxo1 signaling in hepatocellular carcinoma. Cell. Mol. Gastroenterol. Hepatol. 19, 101454 (2024).
Hui, W. et al. Ginkgo biloba extract promotes Treg differentiation to ameliorate ischemic stroke by way of inhibition of HIF-1α/HK2 pathway. Phytother. Res. 37, 5821–5836 (2023).
Lv, Q. et al. Norisoboldine, a pure AhR agonist, promotes Treg differentiation and attenuates colitis by way of focusing on glycolysis and subsequent NAD(+)/SIRT1/SUV39H1/H3K9me3 signaling pathway. Cell Loss of life Dis. 9, 258 (2018).
Procaccini, C. et al. Alerts of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant within the management of Treg cell proliferative potential. Immunity 54, 1543–1560.e1546 (2021).
Court docket, A. C. et al. Mitochondrial switch from MSCs to T cells induces Treg differentiation and restricts inflammatory response. EMBO Rep. 21, e48052 (2020).
Ramos, G. P. et al. G9a modulates lipid metabolism in CD4 T cells to control intestinal irritation. Gastroenterology 164, 256–271.e210 (2023).
Luo, X. et al. Innovative: TGF-beta-induced expression of Foxp3 in T cells is mediated via inactivation of ERK. J. Immunol. 180, 2757–2761 (2008).
Huang, J. et al. Melatonin, an endogenous hormone, modulates Th17 cells by way of the reactive-oxygen species/TXNIP/HIF-1α axis to alleviate autoimmune uveitis. J. Neuroinflammation 19, 124 (2022).
Daenthanasanmak, A. et al. Focusing on Sirt-1 controls GVHD by inhibiting T-cell allo-response and selling Treg stability in mice. Blood 133, 266–279 (2019).
Akamatsu, M. et al. Conversion of antigen-specific effector/reminiscence T cells into Foxp3-expressing T(reg) cells by inhibition of CDK8/19. Sci. Immunol. 4, eaaw2707 (2019).
Dinesh, P. & Rasool, M. Berberine mitigates IL-21/IL-21R mediated autophagic inflow in fibroblast-like synoviocytes and regulates Th17/Treg imbalance in rheumatoid arthritis. Apoptosis 24, 644–661 (2019).
Arai, M. et al. Oral antigen publicity beneath costimulation blockade induces Treg cells to ascertain immune tolerance. J. Exp. Med. 223, e20251635 (2026).
Zhou, H. et al. A peptide encoded by pri-miRNA-31 represses autoimmunity by selling T(reg) differentiation. EMBO Rep. 23, e53475 (2022).
Huang, Q. et al. Bioactive compounds from ShenFuShanYuRou decoction improve Treg cell operate towards hemorrhagic shock damage by way of Stat1- and Gbp5-dependent FOXP3 induction. Clin. Transl. Med. 14, e70047 (2024).
Sawitzki, B. et al. Regulatory cell remedy in kidney transplantation (The ONE Examine): a harmonised design and evaluation of seven non-randomised, single-arm, part 1/2 A trials. Lancet 395, 1627–1639 (2020).
Gauthier, J. M. et al. The rising function of regulatory T cells following lung transplantation. Immunol. Rev. 292, 194–208 (2019).
Zhao, Y. et al. ADAR1 improved Treg cell operate via the miR-21b/Foxp3 axis and inhibits the development of acute graft-versus-host illness after allogeneic hematopoietic stem cell transplantation. Int. Immunopharmacol. 115, 109620 (2023).
Michalek, R. D. et al. Innovative: distinct glycolytic and lipid oxidative metabolic packages are important for effector and regulatory CD4+T cell subsets. J. Immunol. 186, 3299–3303 (2011).
Berod, L. et al. De novo fatty acid synthesis controls the destiny between regulatory T and T helper 17 cells. Nat. Med. 20, 1327–1333 (2014).
Gerriets, V. A. et al. Foxp3 and Toll-like receptor signaling steadiness T(reg) cell anabolic metabolism for suppression. Nat. Immunol. 17, 1459–1466 (2016).
Li, L. et al. TLR8-mediated metabolic management of human treg operate: a mechanistic goal for most cancers immunotherapy. Cell Metab. 29, 103–123.e105 (2019).
Rokade, S., Damani, A. M., Oft, M. & Emmerich, J. IL-2 based mostly most cancers immunotherapies: an evolving paradigm. Entrance. Immunol. 15, 1433989 (2024).
Friedmann, M. C., Migone, T. S., Russell, S. M. & Leonard, W. J. Completely different interleukin 2 receptor beta-chain tyrosines couple to no less than two signaling pathways and synergistically mediate interleukin 2-induced proliferation. Proc. Natl. Acad. Sci. USA. 93, 2077–2082 (1996).