{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T17:00:38Z","timestamp":1785517238227,"version":"3.56.0"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["252623821"],"award-info":[{"award-number":["252623821"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["390873048"],"award-info":[{"award-number":["390873048"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["432325352"],"award-info":[{"award-number":["432325352"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["390873048"],"award-info":[{"award-number":["390873048"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["272482170"],"award-info":[{"award-number":["272482170"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["432325352"],"award-info":[{"award-number":["432325352"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["390685813"],"award-info":[{"award-number":["390685813"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009318","name":"Helmholtz Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009318","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Mol Immunol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells play critical roles in regulating the activity of the germinal center (GC), which is essential for the generation of high-affinity antibodies. In the GC, Tfh cells help B cells to\u00a0proliferate and to\u00a0differentiate into memory B cells and long-lived plasma cells. In contrast, Tfr cells, a specialized subset of regulatory T cells (Tregs), modulate the humoral immune response by suppressing excessive or autoreactive B-cell activity. Here, we established an in vitro differentiation protocol for mouse CD4\u207a T cells that yielded CXCR5\u207aFoxP3\u207a Tfr cells that exhibited a Bcl6\n                    <jats:sup>hi<\/jats:sup>\n                    PD-1\n                    <jats:sup>hi<\/jats:sup>\n                    CD25\n                    <jats:sup>lo<\/jats:sup>\n                    GITR\n                    <jats:sup>int<\/jats:sup>\n                    phenotype and were distinct from Treg and Tfh cells. Functionally, in vitro-generated Tfr cells potently suppressed Tfh cell-driven B-cell class switching to IgG1 and downregulated the expression of B-cell costimulatory ligands. While in vitro-generated\n                    <jats:italic>Bcl6<\/jats:italic>\n                    -deficient Tfh cells were impaired in providing help to B cells for efficient class switching to IgG1, in vitro-generated\n                    <jats:italic>Bcl6<\/jats:italic>\n                    -deficient Tfr cells failed to inhibit Tfh cell-driven B-cell class switching to IgG1. Mechanistically, we showed that Tfr cells emerged from FoxP3\n                    <jats:sup>+<\/jats:sup>\n                    precursors in low-IL-2 environments through a TGF-\u03b2- and c-Maf-dependent pathway, allowing for reprogramming and reinforcement of the follicular regulatory cell program in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells in vitro.\n                  <\/jats:p>","DOI":"10.1038\/s41423-026-01440-9","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:02:52Z","timestamp":1782345772000},"page":"1022-1037","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TGF-\u03b2 and IL-2 differentially shape T follicular regulatory cell differentiation and stability in vitro"],"prefix":"10.1038","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3476-6325","authenticated-orcid":false,"given":"Luisa","family":"Bach","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinshui","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olin","family":"Arteaga Transito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammadamin","family":"Ghasemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa Maria","family":"Steinheuer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3311-5051","authenticated-orcid":false,"given":"Teresa","family":"Steffen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0336-8284","authenticated-orcid":false,"given":"Elena","family":"De Domenico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ulas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9209-3501","authenticated-orcid":false,"given":"F. Thomas","family":"Wunderlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9704-148X","authenticated-orcid":false,"given":"Marc D.","family":"Beyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Thurley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-8288","authenticated-orcid":false,"given":"Dirk","family":"Baumjohann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"1440_CR1","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1146\/annurev-immunol-120419-022408","volume":"40","author":"GD Victora","year":"2022","unstructured":"Victora GD, Nussenzweig MC. Germinal Centers. Annu Rev Immunol. 2022;40:413\u201342.","journal-title":"Annu Rev Immunol"},{"key":"1440_CR2","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1016\/j.immuni.2019.04.011","volume":"50","author":"S Crotty","year":"2019","unstructured":"Crotty S. T Follicular Helper Cell Biology: A Decade of Discovery and Diseases. Immunity. 2019;50:1132\u201348.","journal-title":"Immunity"},{"key":"1440_CR3","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1146\/annurev-immunol-090222-102834","volume":"42","author":"W Song","year":"2024","unstructured":"Song W, Craft J. T Follicular Helper Cell Heterogeneity. Annu Rev Immunol. 2024;42:127\u201352.","journal-title":"Annu Rev Immunol"},{"key":"1440_CR4","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1002\/eji.202049148","volume":"51","author":"D Baumjohann","year":"2021","unstructured":"Baumjohann D, Fazilleau N. Antigen-dependent multistep differentiation of T follicular helper cells and its role in SARS-CoV-2 infection and vaccination. Eur J Immunol. 2021;51:1325\u201333.","journal-title":"Eur J Immunol"},{"key":"1440_CR5","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1038\/s41590-022-01253-8","volume":"23","author":"D Yu","year":"2022","unstructured":"Yu D, Walker LSK, Liu Z, Linterman MA, Li Z. Targeting TFH cells in human diseases and vaccination: rationale and practice. Nat Immunol. 2022;23:1157\u201368.","journal-title":"Nat Immunol"},{"key":"1440_CR6","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1038\/nm.2425","volume":"17","author":"MA Linterman","year":"2011","unstructured":"Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med. 2011;17:975\u201382.","journal-title":"Nat Med"},{"key":"1440_CR7","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/nm.2426","volume":"17","author":"Y Chung","year":"2011","unstructured":"Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011;17:983\u20138.","journal-title":"Nat Med"},{"key":"1440_CR8","doi-asserted-by":"publisher","first-page":"4553","DOI":"10.4049\/jimmunol.1101328","volume":"187","author":"I Wollenberg","year":"2011","unstructured":"Wollenberg I, Agua-Doce A, Hern\u00e1ndez A, Almeida C, Oliveira VG, Faro J, et al. Regulation of the Germinal Center Reaction by Foxp3+ Follicular Regulatory T Cells. J Immunol. 2011;187:4553\u201360.","journal-title":"J Immunol"},{"key":"1440_CR9","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1016\/j.immuni.2014.12.005","volume":"41","author":"PT Sage","year":"2014","unstructured":"Sage PT, Paterson AM, Lovitch SB, Sharpe AH. The coinhibitory receptor CTLA-4 controls B-cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity. 2014;41:1026\u201339.","journal-title":"Immunity"},{"key":"1440_CR10","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1002\/eji.201546094","volume":"46","author":"H Wu","year":"2016","unstructured":"Wu H, Chen Y, Liu H, Xu LL, Teuscher P, Wang S, et al. Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice. Eur J Immunol. 2016;46:1152\u201361.","journal-title":"Eur J Immunol"},{"key":"1440_CR11","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.immuni.2014.05.016","volume":"41","author":"S Kawamoto","year":"2014","unstructured":"Kawamoto S, Maruya M, Kato LM, Suda W, Atarashi K, Doi Y, et al. Foxp3+ T Cells Regulate Immunoglobulin A Selection and Facilitate Diversification of Bacterial Species Responsible for Immune Homeostasis. Immunity. 2014;41:152\u201365.","journal-title":"Immunity"},{"key":"1440_CR12","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1084\/jem.20170901","volume":"215","author":"W Fu","year":"2018","unstructured":"Fu W, Liu X, Lin X, Feng H, Sun L, Li S, et al. Deficiency in T follicular regulatory cells promotes autoimmunity. J Exp Med. 2018;215:815\u201325.","journal-title":"J Exp Med"},{"key":"1440_CR13","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s41232-021-00164-9","volume":"41","author":"H Hao","year":"2021","unstructured":"Hao H, Nakayamada S, Tanaka Y. Differentiation, functions, and roles of T follicular regulatory cells in autoimmune diseases. Inflamm Regen. 2021;41:14.","journal-title":"Inflamm Regen"},{"key":"1440_CR14","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/j.immuni.2014.12.006","volume":"41","author":"JB Wing","year":"2014","unstructured":"Wing JB, Ise W, Kurosaki T, Sakaguchi S. Regulatory T Cells Control Antigen-Specific Expansion of Tfh Cell Number and Humoral Immune Responses via the Coreceptor CTLA-4. Immunity. 2014;41:1013\u201325.","journal-title":"Immunity"},{"key":"1440_CR15","doi-asserted-by":"publisher","first-page":"5191","DOI":"10.1172\/JCI76861","volume":"124","author":"PT Sage","year":"2014","unstructured":"Sage PT, Alvarez D, Godec J, Von Andrian UH, Sharpe AH. Circulating T follicular regulatory and helper cells have memory-like properties. J Clin Invest. 2014;124:5191\u2013204.","journal-title":"J Clin Invest"},{"key":"1440_CR16","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1038\/ni.3578","volume":"17","author":"PT Sage","year":"2016","unstructured":"Sage PT, Ron-Harel N, Juneja VR, Sen DR, Maleri S, Sungnak W, et al. Suppression by TFR cells leads to durable and selective inhibition of B-cell effector function. Nat Immunol. 2016;17:1436\u201346.","journal-title":"Nat Immunol"},{"key":"1440_CR17","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aan4767","volume":"2","author":"BJ Laidlaw","year":"2017","unstructured":"Laidlaw BJ, Lu Y, Amezquita RA, Weinstein JS, Vander Heiden JA, Gupta NT, et al. Interleukin-10 from CD4+ follicular regulatory T cells promotes the germinal center response. Sci Immunol. 2017;2:eaan4767.","journal-title":"Sci Immunol"},{"key":"1440_CR18","doi-asserted-by":"publisher","first-page":"3820","DOI":"10.1172\/JCI132249","volume":"130","author":"MM Xie","year":"2020","unstructured":"Xie MM, Chen Q, Liu H, Yang K, Koh B, Wu H, et al. T follicular regulatory cells and IL-10 promote food antigen\u2013specific IgE. J Clin Invest. 2020;130:3820\u201332.","journal-title":"J Clin Invest"},{"key":"1440_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15067","volume":"8","author":"AR Maceiras","year":"2017","unstructured":"Maceiras AR, Almeida S, Mariotti-Ferrandiz E, Chaara W, Jebbawi F, Six A, et al. T follicular helper and T follicular regulatory cells have different TCR specificity. Nat Commun. 2017;8:15067.","journal-title":"Nat Commun"},{"key":"1440_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10579","volume":"7","author":"M Aloulou","year":"2016","unstructured":"Aloulou M, Carr EJ, Gador M, Bignon A, Liblau RS, Fazilleau N, et al. Follicular regulatory T cells can be specific for the immunizing antigen and derive from na\u00efve T cells. Nat Commun. 2016;7:10579.","journal-title":"Nat Commun"},{"key":"1440_CR21","doi-asserted-by":"publisher","unstructured":"Cavaco MM, Gaspar P, Do Amaral Vieira R, Ribeiro F, Graca L. Heterogeneity of T follicular regulatory cells: exploring their expanding ontogeny and differentiation pathways. ImmunolCell Biol. 2025;70026. https:\/\/doi.org\/10.1111\/imcb.70026.","DOI":"10.1111\/imcb.70026"},{"key":"1440_CR22","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1016\/j.immuni.2011.03.023","volume":"34","author":"YS Choi","year":"2011","unstructured":"Choi YS, Kageyama R, Eto D, Escobar TC, Johnston RJ, Monticelli L, et al. ICOS Receptor Instructs T Follicular Helper Cell versus Effector Cell Differentiation via Induction of the Transcriptional Repressor Bcl6. Immunity. 2011;34:932\u201346.","journal-title":"Immunity"},{"key":"1440_CR23","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/ni.2496","volume":"14","author":"PT Sage","year":"2013","unstructured":"Sage PT, Francisco LM, Carman CV, Sharpe AH. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat Immunol. 2013;14:152\u201361.","journal-title":"Nat Immunol"},{"key":"1440_CR24","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1084\/jem.20130604","volume":"211","author":"M Vaeth","year":"2014","unstructured":"Vaeth M, M\u00fcller G, Stauss D, Dietz L, Klein-Hessling S, Serfling E, et al. Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression. J Exp Med. 2014;211:545\u201361.","journal-title":"J Exp Med"},{"key":"1440_CR25","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1038\/ni1263","volume":"6","author":"JD Fontenot","year":"2005","unstructured":"Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6:1142\u201351.","journal-title":"Nat Immunol"},{"key":"1440_CR26","doi-asserted-by":"publisher","DOI":"10.1126\/science.aao2933","volume":"361","author":"D DiToro","year":"2018","unstructured":"DiToro D, Winstead CJ, Pham D, Witte S, Andargachew R, Singer JR, et al. Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells. Science. 2018;361:eaao2933.","journal-title":"Science"},{"key":"1440_CR27","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1111\/imm.12815","volume":"153","author":"G Yang","year":"2018","unstructured":"Yang G, Yang X, Zhang J, Li G, Zheng D, Peng A, et al. Transcriptional repressor Blimp1 regulates follicular regulatory T-cell homeostasis and function. Immunology. 2018;153:105\u201317.","journal-title":"Immunology"},{"key":"1440_CR28","doi-asserted-by":"publisher","first-page":"107575","DOI":"10.1016\/j.celrep.2020.107575","volume":"31","author":"E Shen","year":"2020","unstructured":"Shen E, Rabe H, Luo L, Wang L, Wang Q, Yin J, et al. Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor. Cell Rep. 2020;31:107575.","journal-title":"Cell Rep"},{"key":"1440_CR29","doi-asserted-by":"publisher","first-page":"6400","DOI":"10.1073\/pnas.1705551114","volume":"114","author":"JB Wing","year":"2017","unstructured":"Wing JB, Kitagawa Y, Locci M, Hume H, Tay C, Morita T, et al. A distinct subpopulation of CD25\u2212 T-follicular regulatory cells localizes in the germinal centers. Proc Natl Acad Sci. 2017;114:6400.","journal-title":"Proc Natl Acad Sci"},{"key":"1440_CR30","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aan0368","volume":"2","author":"PG Ritvo","year":"2017","unstructured":"Ritvo PG, Churlaud G, Quiniou V, Florez L, Brimaud F, Fourcade G, et al. Tfr cells lack IL-2R\u03b1 but express decoy IL-1R2 and IL-1Ra and suppress the IL-1\u2013dependent activation of Tfh cells. Sci Immunol. 2017;2:eaan0368.","journal-title":"Sci Immunol"},{"key":"1440_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14647","volume":"8","author":"C Jandl","year":"2017","unstructured":"Jandl C, Liu SM, Ca\u00f1ete PF, Warren J, Hughes WE, Vogelzang A, et al. IL-21 restricts T follicular regulatory T-cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2. Nat Commun. 2017;8:14647.","journal-title":"Nat Commun"},{"key":"1440_CR32","doi-asserted-by":"publisher","first-page":"e17739","DOI":"10.1371\/journal.pone.0017739","volume":"6","author":"D Eto","year":"2011","unstructured":"Eto D, Lao C, DiToro D, Barnett B, Escobar TC, Kageyama R, et al. IL-21 and IL-6 Are Critical for Different Aspects of B-Cell Immunity and Redundantly Induce Optimal Follicular Helper CD4 T-Cell (Tfh) Differentiation. PLoS ONE. 2011;6:e17739.","journal-title":"PLoS ONE"},{"key":"1440_CR33","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe5146","volume":"373","author":"JT Jacobsen","year":"2021","unstructured":"Jacobsen JT, Hu W, R Castro TB, Solem S, Galante A, Lin Z, et al. Expression of Foxp3 by T follicular helper cells in end-stage germinal centers. Science. 2021;373:eabe5146.","journal-title":"Science"},{"key":"1440_CR34","doi-asserted-by":"publisher","first-page":"eadd4818","DOI":"10.1126\/sciimmunol.add4818","volume":"9","author":"Y Chang","year":"2024","unstructured":"Chang Y, Bach L, Hasiuk M, Wen L, Elmzzahi T, Tsui C, et al. TGF-\u03b2 specifies TFH versus TH 17 cell fates in murine CD4+ T cells through c-Maf. Sci Immunol. 2024;9:eadd4818 4818.","journal-title":"Sci Immunol"},{"key":"1440_CR35","doi-asserted-by":"publisher","first-page":"e2439","DOI":"10.1038\/cddis.2016.348","volume":"7","author":"L Li","year":"2016","unstructured":"Li L, Yang SH, Yao Y, Xie YQ, Yang YQ, Wang YH, et al. Block of both TGF-\u03b2 and IL-2 signaling impedes Neurophilin-1+ regulatory T-cell and follicular regulatory T-cell development. Cell Death Dis. 2016;7:e2439.","journal-title":"Cell Death Dis"},{"key":"1440_CR36","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.1084\/jem.20030152","volume":"198","author":"W Chen","year":"2003","unstructured":"Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of Peripheral CD4+CD25\u2212 Na\u00efve T Cells to CD4+CD25+ Regulatory T Cells by TGF-\u03b2 Induction of Transcription Factor Foxp3. J Exp Med. 2003;198:1875\u201386.","journal-title":"J Exp Med"},{"key":"1440_CR37","doi-asserted-by":"publisher","first-page":"5149","DOI":"10.4049\/jimmunol.172.9.5149","volume":"172","author":"MC Fantini","year":"2004","unstructured":"Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting Edge: TGF-\u03b2 Induces a Regulatory Phenotype in CD4+CD25\u2212 T Cells through Foxp3 Induction and Down-Regulation of Smad7. J Immunol. 2004;172:5149\u201353.","journal-title":"J Immunol"},{"key":"1440_CR38","doi-asserted-by":"publisher","first-page":"4022","DOI":"10.4049\/jimmunol.178.7.4022","volume":"178","author":"TS Davidson","year":"2007","unstructured":"Davidson TS, DiPaolo RJ, Andersson J, Shevach EM. Cutting Edge: IL-2 Is Essential for TGF-\u03b2-Mediated Induction of Foxp3+ T Regulatory Cells. J Immunol. 2007;178:4022\u20136.","journal-title":"J Immunol"},{"key":"1440_CR39","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1016\/j.immuni.2011.07.015","volume":"35","author":"KT Lu","year":"2011","unstructured":"Lu KT, Kanno Y, Cannons JL, Handon R, Bible P, Elkahloun AG, et al. Functional and Epigenetic Studies Reveal Multistep Differentiation and Plasticity of In Vitro-Generated and In Vivo-Derived Follicular T Helper Cells. Immunity. 2011;35:622\u201332.","journal-title":"Immunity"},{"key":"1440_CR40","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/ni.1690","volume":"10","author":"AT Bauquet","year":"2009","unstructured":"Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho IC, Sharpe AH, et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol. 2009;10:167\u201375.","journal-title":"Nat Immunol"},{"key":"1440_CR41","doi-asserted-by":"publisher","first-page":"3734","DOI":"10.4049\/jimmunol.1103246","volume":"188","author":"MA Kroenke","year":"2012","unstructured":"Kroenke MA, Eto D, Locci M, Cho M, Davidson T, Haddad EK, et al. Bcl6 and Maf Cooperate To Instruct Human Follicular Helper CD4 T-Cell Differentiation. J Immunol. 2012;188:3734\u201344.","journal-title":"J Immunol"},{"key":"1440_CR42","doi-asserted-by":"publisher","first-page":"480","DOI":"10.3389\/fimmu.2017.00480","volume":"8","author":"F Andris","year":"2017","unstructured":"Andris F, Denanglaire S, Anciaux M, Hercor M, Hussein H, Leo O. The Transcription Factor c-Maf Promotes the Differentiation of Follicular Helper T Cells. Front Immunol. 2017;8:480.","journal-title":"Front Immunol"},{"key":"1440_CR43","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1111\/imr.12739","volume":"288","author":"VR Fonseca","year":"2019","unstructured":"Fonseca VR, Ribeiro F, Graca L. T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr-cell compartments. Immunol Rev. 2019;288:112\u201327.","journal-title":"Immunol Rev"},{"key":"1440_CR44","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1016\/j.immuni.2012.02.012","volume":"36","author":"A Ballesteros-Tato","year":"2012","unstructured":"Ballesteros-Tato A, Le\u00f3n B, Graf BA, Moquin A, Adams PS, Lund FE, et al. Interleukin-2 Inhibits Germinal Center Formation by Limiting T Follicular Helper Cell Differentiation. Immunity. 2012;36:847\u201356.","journal-title":"Immunity"},{"key":"1440_CR45","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1084\/jem.20111174","volume":"209","author":"RJ Johnston","year":"2012","unstructured":"Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S. STAT5 is a potent negative regulator of TFH cell differentiation. J Exp Med. 2012;209:243\u201350.","journal-title":"J Exp Med"},{"key":"1440_CR46","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1038\/ni.3837","volume":"18","author":"D Botta","year":"2017","unstructured":"Botta D, Fuller MJ, Marquez-Lago TT, Bachus H, Bradley JE, Weinmann AS, et al. Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat Immunol. 2017;18:1249\u201360.","journal-title":"Nat Immunol"},{"key":"1440_CR47","doi-asserted-by":"publisher","first-page":"3931","DOI":"10.4049\/jimmunol.1701134","volume":"199","author":"JD Wheaton","year":"2017","unstructured":"Wheaton JD, Yeh C-H, Ciofani M. Cutting Edge: c-Maf Is Required for Regulatory T Cells To Adopt ROR\u03b3t+ and Follicular Phenotypes. J Immunol. 2017;199:3931\u20136.","journal-title":"J Immunol"},{"key":"1440_CR48","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1126\/science.1176676","volume":"325","author":"RI Nurieva","year":"2009","unstructured":"Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, et al. Bcl6 mediates the development of T follicular helper cells. Science. 2009;325:1001\u20135.","journal-title":"Science"},{"key":"1440_CR49","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1126\/science.1175870","volume":"325","author":"RJ Johnston","year":"2009","unstructured":"Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, et al. Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation. Science. 2009;325:1006\u201310.","journal-title":"Science"},{"key":"1440_CR50","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.immuni.2009.07.002","volume":"31","author":"D Yu","year":"2009","unstructured":"Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL, et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity. 2009;31:457\u201368.","journal-title":"Immunity"},{"key":"1440_CR51","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/nature12910","volume":"507","author":"X Liu","year":"2014","unstructured":"Liu X, Chen X, Zhong B, Wang A, Wang X, Chu F, et al. Transcription factor achaete-scute homolog 2 initiates follicular T-helper-cell development. Nature. 2014;507:513\u20138.","journal-title":"Nature"},{"key":"1440_CR52","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.128076","volume":"4","author":"MM Xie","year":"2019","unstructured":"Xie MM, Fang S, Chen Q, Liu H, Wan J, Dent AL. Follicular regulatory T cells inhibit the development of granzyme B\u2013expressing follicular helper T cells. JCI Insight. 2019;4:e128076.","journal-title":"JCI Insight"},{"key":"1440_CR53","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1038\/ni.1899","volume":"11","author":"KM Murphy","year":"2010","unstructured":"Murphy KM, Stockinger B. Effector T-cell plasticity: flexibility in the face of changing circumstances. Nat Immunol. 2010;11:674\u201380.","journal-title":"Nat Immunol"},{"key":"1440_CR54","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1002\/art.41457","volume":"73","author":"H Hao","year":"2021","unstructured":"Hao H, Nakayamada S, Yamagata K, Ohkubo N, Iwata S, Inoue Y, et al. Conversion of T Follicular Helper Cells to T Follicular Regulatory Cells by Interleukin-2 Through Transcriptional Regulation in Systemic Lupus Erythematosus. Arthritis Rheumatol. 2021;73:132\u201342.","journal-title":"Arthritis Rheumatol"},{"key":"1440_CR55","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.ade8162","volume":"8","author":"C Le Coz","year":"2023","unstructured":"Le Coz C, Oldridge DA, Herati RS, De Luna N, Garifallou J, Cruz Cabrera E, et al. Human T follicular helper clones seed the germinal center\u2013resident regulatory pool. Sci Immunol. 2023;8:eade8162.","journal-title":"Sci Immunol"},{"key":"1440_CR56","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1126\/science.1191996","volume":"329","author":"YP Rubtsov","year":"2010","unstructured":"Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, et al. Stability of the regulatory T-cell lineage in vivo. Science. 2010;329:1667\u201371.","journal-title":"Science"},{"key":"1440_CR57","doi-asserted-by":"publisher","first-page":"3981","DOI":"10.1016\/j.cell.2021.05.028","volume":"184","author":"HS Wong","year":"2021","unstructured":"Wong HS, Park K, Gola A, Baptista AP, Miller CH, Deep D, et al. A local regulatory T-cell feedback circuit maintains immune homeostasis by pruning self-activated T cells. Cell. 2021;184:3981\u2013.e22.","journal-title":"Cell"},{"key":"1440_CR58","doi-asserted-by":"publisher","first-page":"110134","DOI":"10.1016\/j.isci.2024.110134","volume":"27","author":"P Brunner","year":"2024","unstructured":"Brunner P, Kiwitz L, Li L, Thurley K. Diffusion-limited cytokine signaling in T-cell populations. iScience. 2024;27:110134.","journal-title":"iScience"},{"key":"1440_CR59","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/s41590-018-0083-5","volume":"19","author":"L Gabry\u0161ov\u00e1","year":"2018","unstructured":"Gabry\u0161ov\u00e1 L, et al. c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells. Nat Immunol. 2018;19:497\u2013507.","journal-title":"Nat Immunol"},{"key":"1440_CR60","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1038\/ni1536","volume":"8","author":"P Pandiyan","year":"2007","unstructured":"Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation\u2013mediated apoptosis of effector CD4+ T cells. Nat Immunol. 2007;8:1353\u201362.","journal-title":"Nat Immunol"},{"key":"1440_CR61","doi-asserted-by":"publisher","first-page":"3058","DOI":"10.1073\/pnas.0812851107","volume":"107","author":"D Busse","year":"2010","unstructured":"Busse D, de la Rosa M, Hobiger K, Thurley K, Flossdorf M, Scheffold A, et al. Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments. Proc Natl Acad Sci. 2010;107:3058\u201363.","journal-title":"Proc Natl Acad Sci"},{"key":"1440_CR62","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/nature17947","volume":"533","author":"J Li","year":"2016","unstructured":"Li J, Lu E, Yi T, Cyster JG. EBI2 augments Tfh cell fate by promoting interaction with IL-2-quenching dendritic cells. Nature. 2016;533:110\u20134.","journal-title":"Nature"},{"key":"1440_CR63","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/ni.1715","volume":"10","author":"RL Reinhardt","year":"2009","unstructured":"Reinhardt RL, Liang H-E, Locksley RM. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol. 2009;10:385\u201393.","journal-title":"Nat Immunol"},{"key":"1440_CR64","doi-asserted-by":"publisher","first-page":"e39750","DOI":"10.1371\/journal.pone.0039750","volume":"7","author":"AE Price","year":"2012","unstructured":"Price AE, Reinhardt RL, Liang H-E, Locksley RM. Marking and quantifying IL-17A-producing cells in vivo. PloS ONE. 2012;7:e39750.","journal-title":"PloS ONE"},{"key":"1440_CR65","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.immuni.2011.12.012","volume":"36","author":"T Miyao","year":"2012","unstructured":"Miyao T, Floess S, Setoguchi R, Luche H, Fehling H, Waldmann H, et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity. 2012;36:262\u201375.","journal-title":"Immunity"},{"key":"1440_CR66","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001674","volume":"11","author":"A \u015aledzi\u0144ska","year":"2013","unstructured":"\u015aledzi\u0144ska A, Hemmers S, Mair F, Gorka O, Ruland J, Fairbairn L, et al. TGF-\u03b2 signaling is required for CD4+ T-cell homeostasis but dispensable for regulatory T-cell function. PLoS Biol. 2013;11:e1001674.","journal-title":"PLoS Biol"},{"key":"1440_CR67","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1182\/blood.V100.2.560","volume":"100","author":"P Leve\u0301en","year":"2002","unstructured":"Leve\u0301en P, Larsson J, Ehinger M, Cilio CM, Sundler M, Sj\u00f6strand LJ, et al. Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood. 2002;100:560\u20138.","journal-title":"Blood"},{"key":"1440_CR68","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1126\/science.1214314","volume":"335","author":"H Wende","year":"2012","unstructured":"Wende H, Lechner SG, Cheret C, Bourane S, Kolanczyk ME, Pattyn A, et al. The transcription factor c-Maf controls touch receptor development and function. Science. 2012;335:1373\u20136.","journal-title":"Science"},{"key":"1440_CR69","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1016\/S1074-7613(01)00227-8","volume":"15","author":"PP Lee","year":"2001","unstructured":"Lee PP, Fitzpatrick DR, Beard C, Jessup HK, Lehar S, Makar KW, et al. A critical role for Dnmt1 and DNA methylation in T-cell development, function, and survival. Immunity. 2001;15:763\u201374.","journal-title":"Immunity"},{"key":"1440_CR70","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1016\/j.immuni.2008.02.017","volume":"28","author":"YP Rubtsov","year":"2008","unstructured":"Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, et al. Regulatory T-Cell-Derived Interleukin-10 Limits Inflammation at Environmental Interfaces. Immunity. 2008;28:546\u201358.","journal-title":"Immunity"},{"key":"1440_CR71","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1038\/s41593-021-00854-0","volume":"24","author":"N Biglari","year":"2021","unstructured":"Biglari N, Gaziano I, Schumacher J, Radermacher J, Paeger L, Klemm P, et al. Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting. Nat Neurosci. 2021;24:913\u201329.","journal-title":"Nat Neurosci"},{"key":"1440_CR72","doi-asserted-by":"publisher","first-page":"2708","DOI":"10.1002\/eji.202170126","volume":"51","author":"A Cossarizza","year":"2021","unstructured":"Cossarizza A, Chang HD, Radbruch A, Abrignani S, Addo R, Akdis M, et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition). Eur J Immunol. 2021;51:2708\u20133145.","journal-title":"Eur J Immunol"},{"key":"1440_CR73","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/978-1-4939-2498-1_3","volume":"1291","author":"D Baumjohann","year":"2015","unstructured":"Baumjohann D, Ansel KM. Tracking early T follicular helper cell differentiation in vivo. Methods Mol Biol Clifton NJ. 2015;1291:27\u201338.","journal-title":"Methods Mol Biol Clifton NJ"}],"container-title":["Cellular &amp; Molecular Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41423-026-01440-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41423-026-01440-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41423-026-01440-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T16:11:34Z","timestamp":1785514294000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41423-026-01440-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":73,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["1440"],"URL":"https:\/\/doi.org\/10.1038\/s41423-026-01440-9","relation":{},"ISSN":["2042-0226"],"issn-type":[{"value":"2042-0226","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]},"assertion":[{"value":"9 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}