{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:06:21Z","timestamp":1792782381488,"version":"4.5.0"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universidade Federal De Minas Gerais","id":[{"id":"https:\/\/ror.org\/0176yjw32","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Inflamm. Res."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The role of regulatory T cells (Tregs) in\n                      <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                      infection remains unresolved, with conflicting evidence suggesting either protection from immunopathology or impairment of parasite control.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed the first systematic review integrating data on Treg phenotype and function in human and experimental Chagas disease. A comprehensive search of PubMed, Embase, Scopus, and LILACS (2003\u20132025) identified studies assessing Tregs during\n                      <jats:italic>T. cruzi<\/jats:italic>\n                      infection. Study selection, data extraction, and risk-of-bias assessment followed PRISMA 2020 and Cochrane guidelines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Twenty-seven studies met eligibility criteria (9 human, 18 murine). Human studies consistently showed that individuals with indeterminate Chagas disease harbor functionally stable Tregs enriched for CD39, CD25\n                      <jats:sup>high<\/jats:sup>\n                      , and CTLA-4 expression. In contrast, Chagas cardiomyopathy was associated with Treg instability, PD-1 upregulation, and partial acquisition of Th1-like features. Murine models revealed a phase-dependent role: transient Treg restriction during acute infection enhanced CD8\u207a T cell\u2013mediated parasite control, whereas failure to re-establish regulatory balance promoted chronic cardiac inflammation. Key modulatory pathways included IL-10, IL-2, IL-33\/ST2, G-CSF, and CD39.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings support a dual-role model in which Tregs dynamically coordinate disease tolerance. Treg-associated signatures, particularly CD39 expression and activated\/resting Treg ratios, emerge as promising biomarkers and therapeutic targets for Chagas disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00011-026-02330-6","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:26:53Z","timestamp":1791826013000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dynamics and functional heterogeneity of FOXP3+\u2009regulatory T cells in Trypanosoma cruzi infection: a systematic review"],"prefix":"10.1007","volume":"75","author":[{"given":"Marcelo Eduardo","family":"Cardozo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyane Martins","family":"Cirilo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Laura Grossi","family":"de Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Rafaela","family":"Antunes-Porto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa Vitor","family":"do Braga Amaral","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Bryan","family":"da Rocha Rihs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa Mour\u00e3o","family":"Dias Magalh\u00e3es","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian Lacerda","family":"Bueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9272-5209","authenticated-orcid":false,"given":"Fabiana Sim\u00e3o","family":"Machado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4713-575X","authenticated-orcid":false,"given":"Ricardo Toshio","family":"Fujiwara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"2330_CR1","doi-asserted-by":"crossref","unstructured":"Cousin E, Nascimento BR, Whisnant JL, Zimsen SRM, Harris AA, Machado IE et al. Global, regional, and national burden of Chagas disease, 1990\u20132023: a systematic analysis for the Global Burden of Disease Study 2023. The Lancet Infectious Diseases. 2025;S1473309925005626.","DOI":"10.2139\/ssrn.5381800"},{"issue":"10422","key":"2330_CR2","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/S0140-6736(23)01787-7","volume":"403","author":"AS De Sousa","year":"2024","unstructured":"De Sousa AS, Vermeij D, Ramos AN, Luquetti AO. Chagas disease. Lancet. 2024;403(10422):203\u201318.","journal-title":"Lancet"},{"issue":"5\u20136","key":"2330_CR3","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/S0020-7519(01)00158-8","volume":"31","author":"RL Tarleton","year":"2001","unstructured":"Tarleton RL. Parasite persistence in the aetiology of Chagas disease. Int J Parasitol. 2001;31(5\u20136):550\u20134.","journal-title":"Int J Parasitol"},{"key":"2330_CR4","doi-asserted-by":"crossref","unstructured":"Magalh\u00e3es LMD, Gollob KJ, Zingales B, Dutra WO. Pathogen diversity, immunity, and the fate of infections: lessons learned from Trypanosoma cruzi human\u2013host interactions. Lancet Microbe. 2022 Sept;3(9):e711\u201322.","DOI":"10.1016\/S2666-5247(21)00265-2"},{"issue":"11","key":"2330_CR5","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.pt.2019.08.006","volume":"35","author":"EV Acosta Rodr\u00edguez","year":"2019","unstructured":"Acosta Rodr\u00edguez EV, Araujo Furlan CL, Fiocca Vernengo F, Montes CL, Gruppi A. Understanding CD8\u2009+\u2009T Cell Immunity to Trypanosoma cruzi and How to Improve It. Trends Parasitol. 2019;35(11):899\u2013917.","journal-title":"Trends Parasitol"},{"issue":"1","key":"2330_CR6","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1186\/s12967-022-03761-5","volume":"20","author":"GG Almeida","year":"2022","unstructured":"Almeida GG, Rimkute I, Do Vale INPC, Liechti T, Henriques PM, Roffe E, et al. Chagasic cardiomyopathy is marked by a unique signature of activated CD4\u2009+\u2009T cells. J Transl Med. 2022;20(1):551.","journal-title":"J Transl Med"},{"issue":"3","key":"2330_CR7","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","volume":"155","author":"S Sakaguchi","year":"1995","unstructured":"Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151\u201364.","journal-title":"J Immunol"},{"key":"2330_CR8","doi-asserted-by":"crossref","unstructured":"Sumida TS, Cheru NT, Hafler DA. The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases. Nat Rev Immunol. 2024 July;24(7):503\u201317.","DOI":"10.1038\/s41577-024-00994-x"},{"issue":"1","key":"2330_CR9","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/83784","volume":"27","author":"ME Brunkow","year":"2001","unstructured":"Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, et al. Disruption of a new forkhead\/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27(1):68\u201373.","journal-title":"Nat Genet"},{"key":"2330_CR10","doi-asserted-by":"publisher","first-page":"1650451","DOI":"10.3389\/fimmu.2025.1650451","volume":"16","author":"BE Jugder","year":"2025","unstructured":"Jugder BE, Park E, Du L, Jawale C, Popov N, Guo Z, et al. Tissue-specific roles of regulatory T cells: mechanisms of suppression and beyond along with emerging therapeutic insights in autoimmune indications. Front Immunol. 2025;16:1650451.","journal-title":"Front Immunol"},{"key":"2330_CR11","doi-asserted-by":"crossref","unstructured":"Mu\u00f1oz-Rojas AR, Mathis D. Tissue regulatory T cells: regulatory chameleons. Nat Rev Immunol. 2021 Sept;21(9):597\u2013611.","DOI":"10.1038\/s41577-021-00519-w"},{"key":"2330_CR12","doi-asserted-by":"crossref","unstructured":"Lui PP, Cho I, Ali N. Tissue regulatory T cells. Immunology. 2020 Sept;161(1):4\u201317.","DOI":"10.1111\/imm.13208"},{"key":"2330_CR13","doi-asserted-by":"crossref","unstructured":"Guedes PMM, Gutierrez FRS, Silva GK, Dellalibera-Joviliano R, Rodrigues GJ, Bendhack LM et al. Deficient Regulatory T Cell Activity and Low Frequency of IL-17-Producing T Cells Correlate with the Extent of Cardiomyopathy in Human Chagas\u2019 Disease. Gazzinelli RT, editor. PLoS Negl Trop Dis. 2012;6(4):e1630.","DOI":"10.1371\/journal.pntd.0001630"},{"issue":"4","key":"2330_CR14","doi-asserted-by":"publisher","first-page":"e12650","DOI":"10.1111\/sji.12650","volume":"87","author":"MS Almeida","year":"2018","unstructured":"Almeida MS, Lorena VMB, Medeiros CDA, Junior WO, Cavalcanti MDGAM, Martins SM, et al. Alternative Th17 and CD4+ CD25+ FoxP3+ cell frequencies increase and correlate with worse cardiac function in Chagas cardiomyopathy. Scand J Immunol. 2018;87(4):e12650.","journal-title":"Scand J Immunol"},{"key":"2330_CR15","doi-asserted-by":"crossref","unstructured":"Araujo Furlan CL, Boccardo S, Rodriguez C, Mary VS, Gimenez CMS, Robson SC et al. CD39 expression by regulatory T cells participates in CD8\u2009+\u2009T cell suppression during experimental Trypanosoma cruzi infection. Taylor MC, editor. PLoS Pathog. 2024;20(4):e1012191.","DOI":"10.1371\/journal.ppat.1012191"},{"key":"2330_CR16","doi-asserted-by":"crossref","unstructured":"Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;n71.","DOI":"10.1136\/bmj.n71"},{"issue":"2","key":"2330_CR17","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/nri1012","volume":"3","author":"J Bell","year":"2003","unstructured":"Bell J. Leading role for FOXP3. Nat Rev Immunol. 2003;3(2):95\u201395.","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"2330_CR18","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","volume":"5","author":"M Ouzzani","year":"2016","unstructured":"Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan\u2014a web and mobile app for systematic reviews. Syst Rev. 2016;5(1):210.","journal-title":"Syst Rev"},{"key":"2330_CR19","doi-asserted-by":"crossref","unstructured":"Medeiros NI, Oliveira DS, Ferreira KS, Keesen TSL, Rocha LPC, Sousa GR, et al. FOXP3 gene polymorphisms are associated with indeterminate clinical form of Chagas disease. Microbes Infect. 2025 Sept;27(7):105544.","DOI":"10.1016\/j.micinf.2025.105544"},{"key":"2330_CR20","doi-asserted-by":"publisher","first-page":"750876","DOI":"10.3389\/fcvm.2022.750876","volume":"9","author":"BF Pinto","year":"2022","unstructured":"Pinto BF, Medeiros NI, Teixeira-Carvalho A, Fiuza JA, Eloi-Santos SM, Nunes MCP, et al. Modulation of Regulatory T Cells Activity by Distinct CD80 and CD86 Interactions With CD28\/CTLA-4 in Chagas Cardiomyopathy. Front Cardiovasc Med. 2022;9:750876.","journal-title":"Front Cardiovasc Med"},{"key":"2330_CR21","doi-asserted-by":"crossref","unstructured":"Llaguno M, Da Silva MV, Batista LR, Da Silva DAA, De Sousa RC, De Resende LAPR et al. T-Cell Immunophenotyping and Cytokine Production Analysis in Patients with Chagas Disease 4 Years after Benznidazole Treatment. Herbert DR, editor. Infect Immun. 2019;87(8):e00103-19.","DOI":"10.1128\/IAI.00103-19"},{"key":"2330_CR22","doi-asserted-by":"crossref","unstructured":"Damasio MPS, Rocha MOC, Sousa GR, Ferreira KS, Fares-Gusm\u00e3o RCG, Medeiros NI, et al. PD1 and PDL1 molecules control suppressor activity of regulatory T cells in chronic Chagas cardiomyopathy patients. Hum Immunol. 2019 July;80(7):517\u201322.","DOI":"10.1016\/j.humimm.2019.03.009"},{"key":"2330_CR23","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.actatropica.2016.09.010","volume":"164","author":"A Vallejo","year":"2016","unstructured":"Vallejo A, Monge-Maillo B, Guti\u00e9rrez C, Norman FF, L\u00f3pez-V\u00e9lez R, P\u00e9rez-Molina JA. Changes in the immune response after treatment with benznidazole versus no treatment in patients with chronic indeterminate Chagas disease. Acta Trop. 2016;164:117\u201324.","journal-title":"Acta Trop"},{"issue":"8","key":"2330_CR24","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1016\/j.imbio.2012.04.008","volume":"217","author":"FF De Ara\u00fajo","year":"2012","unstructured":"De Ara\u00fajo FF, Corr\u00eaa-Oliveira R, Rocha MOC, Chaves AT, Fiuza JA, Fares RCG, et al. Foxp3\u2009+\u2009CD25high CD4\u2009+\u2009regulatory T cells from indeterminate patients with Chagas disease can suppress the effector cells and cytokines and reveal altered correlations with disease severity. Immunobiology. 2012;217(8):768\u201377.","journal-title":"Immunobiology"},{"key":"2330_CR25","doi-asserted-by":"publisher","unstructured":"Cardozo ME, Cirilo TM, Souza JLN, Rihs JBR, Duval IB et al. IL-33\/ST2 signaling protects the heart by restraining inflammation and parasite burden during Trypanosoma cruzi experimental infection. Calderon F, editor. ACS Infec Dis. 2025 Dec. https:\/\/doi.org\/10.1021\/acsinfecdis.5c00859","DOI":"10.1021\/acsinfecdis.5c00859"},{"key":"2330_CR26","doi-asserted-by":"crossref","unstructured":"Boccardo S, Rodriguez C, Gimenez CMS, Araujo Furlan CL, Abrate CP, Almada L et al. Dynamics of tissue repair regulatory T cells and damage in acute Trypanosoma cruzi infection. Almeida IC, editor. PLoS Pathog. 2025;21(1):e1012906.","DOI":"10.1371\/journal.ppat.1012906"},{"key":"2330_CR27","doi-asserted-by":"publisher","first-page":"631","DOI":"10.3389\/fimmu.2019.00631","volume":"10","author":"LF Ambrosio","year":"2019","unstructured":"Ambrosio LF, Insfran C, Volpini X, Acosta Rodriguez E, Serra HM, Quintana FJ, et al. Role of Aryl Hydrocarbon Receptor (AhR) in the Regulation of Immunity and Immunopathology During Trypanosoma cruzi Infection. Front Immunol. 2019;10:631.","journal-title":"Front Immunol"},{"key":"2330_CR28","doi-asserted-by":"crossref","unstructured":"Pereira RD, Rabelo RAN, Leite PG, Cramer A, Botelho AFM, Cruz JS, et al. Role of formyl peptide receptor 2 (FPR2) in modulating immune response and heart inflammation in an experimental model of acute and chronic Chagas disease. Cell Immunol. 2021 Nov;369:104427.","DOI":"10.1016\/j.cellimm.2021.104427"},{"key":"2330_CR29","doi-asserted-by":"crossref","unstructured":"Ambrosio LF, Volpini X, Quiroz JN, Brugo MB, Knubel CP, Herrera MR, et al. Association between altered tryptophan metabolism, plasma aryl hydrocarbon receptor agonists, and inflammatory Chagas disease. Front Immunol. 2024 Jan;14:1267641.","DOI":"10.3389\/fimmu.2023.1267641"},{"key":"2330_CR30","doi-asserted-by":"publisher","first-page":"2555","DOI":"10.3389\/fimmu.2018.02555","volume":"9","author":"CL Araujo Furlan","year":"2018","unstructured":"Araujo Furlan CL, Tosello Boari J, Rodriguez C, Canale FP, Fiocca Vernengo F, Boccardo S, et al. Limited Foxp3\u2009+\u2009Regulatory T Cells Response During Acute Trypanosoma cruzi Infection Is Required to Allow the Emergence of Robust Parasite-Specific CD8\u2009+\u2009T Cell Immunity. Front Immunol. 2018;9:2555.","journal-title":"Front Immunol"},{"key":"2330_CR31","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.3389\/fimmu.2017.01548","volume":"8","author":"M Gorosito Serran","year":"2017","unstructured":"Gorosito Serran M, Tosello BJ, Fiocca V, Beccar\u00eda CG, Ramello MC, Bermejo DA, et al. Unconventional pro-inflammatory CD4\u2009+\u2009T cell response in B cell-deficient mice infected with Trypanosoma cruzi. Front Immunol. 2017;8:1548.","journal-title":"Front Immunol"},{"key":"2330_CR32","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.3389\/fimmu.2017.01213","volume":"8","author":"TS Medina","year":"2017","unstructured":"Medina TS, Oliveira GG, Silva MC, David BA, Silva GK, Fonseca DM, et al. Ebi3 prevents Trypanosoma cruzi-induced myocarditis by dampening IFN-\u03b3-driven inflammation. Front Immunol. 2017;8:1213.","journal-title":"Front Immunol"},{"issue":"35","key":"2330_CR33","doi-asserted-by":"publisher","first-page":"58003","DOI":"10.18632\/oncotarget.18217","volume":"8","author":"E Prochetto","year":"2017","unstructured":"Prochetto E, Rold\u00e1n C, Bontempi IA, Bertona D, Peverengo L, Vicco MH, et al. Trans-sialidase-based vaccine candidate protects against Trypanosoma cruzi infection, not only inducing an effector immune response but also affecting cells with regulatory\/suppressor phenotype. Oncotarget. 2017;8(35):58003.","journal-title":"Oncotarget"},{"key":"2330_CR34","doi-asserted-by":"crossref","unstructured":"Ersching J, Basso AS, Kalich VLG, Bortoluci KR, Rodrigues MM. A human trypanosome suppresses CD8\u2009+\u2009T cell priming by dendritic cells through the induction of immune regulatory CD4\u2009+\u2009Foxp3+ T cells. PLoS Pathog. 2016;12(6):e1005698.","DOI":"10.1371\/journal.ppat.1005698"},{"issue":"1","key":"2330_CR35","doi-asserted-by":"publisher","first-page":"e0004285","DOI":"10.1371\/journal.pntd.0004285","volume":"10","author":"FB Gonz\u00e1lez","year":"2016","unstructured":"Gonz\u00e1lez FB, Calmon-Hamaty F, N\u00f4 Seara Cordeiro S, Fern\u00e1ndez Bussy R, Spinelli SV, D\u2019Attilio L, et al. Trypanosoma cruzi Experimental Infection Impacts on the Thymic Regulatory T Cell Compartment. Fujiwara RT, editor. PLoS Negl Trop Dis. 2016;10(1):e0004285.","journal-title":"PLoS Negl Trop Dis"},{"key":"2330_CR36","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.bbi.2014.11.016","volume":"45","author":"FB Gonz\u00e1lez","year":"2015","unstructured":"Gonz\u00e1lez FB, Villar SR, Bussy RF, Martin GH, P\u00e9rol L, Manarin R, et al. Immunoendocrine dysbalance during uncontrolled T. cruzi infection is associated with the acquisition of a Th-1-like phenotype by Foxp3\u2009+\u2009T cells. Brain Behav Immun. 2015;45:219\u201332.","journal-title":"Brain Behav Immun"},{"issue":"3","key":"2330_CR37","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1007\/s00436-014-4300-3","volume":"114","author":"KM Bonney","year":"2015","unstructured":"Bonney KM, Taylor JM, Thorp EB, Epting CL, Engman DM. Depletion of regulatory T cells decreases cardiac parasitosis and inflammation in experimental Chagas disease. Parasitol Res. 2015;114(3):1167\u201378.","journal-title":"Parasitol Res"},{"issue":"12","key":"2330_CR38","doi-asserted-by":"publisher","first-page":"4691","DOI":"10.1096\/fj.13-229351","volume":"27","author":"JF Vasconcelos","year":"2013","unstructured":"Vasconcelos JF, Souza BSF, Lins TFS, Garcia LMS, Kaneto CM, Sampaio GP, et al. Administration of granulocyte colony-stimulating factor induces immunomodulation, recruitment of T regulatory cells, reduction of myocarditis and decrease of parasite load in a mouse model of chronic Chagas disease cardiomyopathy. FASEB J. 2013;27(12):4691\u2013702.","journal-title":"FASEB J"},{"key":"2330_CR39","doi-asserted-by":"crossref","unstructured":"Sanoja C, Carbajosa S, Fresno M, Girones N. Analysis of the dynamics of infiltrating CD4\u2009+\u2009T cell subsets in the heart during experimental Trypanosoma cruzi infection. PLoS ONE. 2013;8(6):e65820.","DOI":"10.1371\/journal.pone.0065820"},{"key":"2330_CR40","doi-asserted-by":"crossref","unstructured":"Flores-Garc\u00eda Y, Rosales-Encina JL, Rosales-Garc\u00eda VH, Satoskar AR, Talam\u00e1s-Rohana P. CD4\u2009+\u2009CD25+ FOXP3\u2009+\u2009Treg cells induced by rSSP4 derived from T. cruzi amastigotes increase parasitemia in an experimental Chagas disease model. BioMed Res Int. 2013(1):632436.","DOI":"10.1155\/2013\/632436"},{"key":"2330_CR41","doi-asserted-by":"crossref","unstructured":"Knubel CP, Martinez FF, Acosta Rodriguez EV, Altamirano A, Rivarola HW, Diaz Lujan C et al. 3-Hydroxy kynurenine treatment controls T. cruzi replication and the inflammatory pathology preventing the clinical symptoms of chronic Chagas disease. PLoS ONE. 2011;6(10):e26550.","DOI":"10.1371\/journal.pone.0026550"},{"issue":"12","key":"2330_CR42","doi-asserted-by":"publisher","first-page":"2934","DOI":"10.1016\/j.immuni.2025.11.011","volume":"58","author":"C Benoist","year":"2025","unstructured":"Benoist C, Vignali DA, Flavell RA. Mathis. The history and promise of Treg cells. Immunity. 2025;58(12):2934\u20139.","journal-title":"Immunity"},{"issue":"2","key":"2330_CR43","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1038\/s41590-018-0280-2","volume":"20","author":"B Akkaya","year":"2019","unstructured":"Akkaya B, Oya Y, Akkaya M, Al Souz J, Holstein AH, Kamenyeva O, et al. Regulatory T cells mediate specific suppression by depleting peptide\u2013MHC class II from dendritic cells. Nat Immunol. 2019;20(2):218\u201331.","journal-title":"Nat Immunol"},{"issue":"6740","key":"2330_CR44","doi-asserted-by":"publisher","first-page":"eadk3248","DOI":"10.1126\/science.adk3248","volume":"387","author":"DE Klawon","year":"2025","unstructured":"Klawon DE, Pagane N, Walker MT, Ganci NK, Miller CH, Gai E, et al. Regulatory T cells constrain T cells of shared specificity to enforce tolerance during infection. Science. 2025;387(6740):eadk3248.","journal-title":"Science"},{"key":"2330_CR45","doi-asserted-by":"publisher","first-page":"1351405","DOI":"10.3389\/fimmu.2024.1351405","volume":"15","author":"S Wachtendorf","year":"2024","unstructured":"Wachtendorf S, Jonin F, Ochel A, Heinrich F, Westendorf AM, Tiegs G, et al. The ST2\u2009+\u2009Treg\/amphiregulin axis protects from immune-mediated hepatitis. Front Immunol. 2024;15:1351405.","journal-title":"Front Immunol"},{"issue":"1","key":"2330_CR46","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1186\/1479-5876-8-113","volume":"8","author":"E d\u2019Hennezel","year":"2010","unstructured":"d\u2019Hennezel E, Kornete M, Piccirillo CA. IL-2 as a therapeutic target for the restoration of Foxp3\u2009+\u2009regulatory T cell function in organ-specific autoimmunity: implications in pathophysiology and translation to human disease. J Transl Med. 2010;8(1):113.","journal-title":"J Transl Med"},{"issue":"1","key":"2330_CR47","doi-asserted-by":"publisher","first-page":"280","DOI":"10.4049\/jimmunol.178.1.280","volume":"178","author":"MA Burchill","year":"2007","unstructured":"Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. IL-2 Receptor \u03b2-Dependent STAT5 Activation Is Required for the Development of Foxp3\u2009+\u2009Regulatory T Cells. J Immunol. 2007;178(1):280\u201390.","journal-title":"J Immunol"},{"issue":"4","key":"2330_CR48","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.cytogfr.2006.05.002","volume":"17","author":"A Franzke","year":"2006","unstructured":"Franzke A. The role of G-CSF in adaptive immunity. Cytokine Growth Factor Rev. 2006;17(4):235\u201344.","journal-title":"Cytokine Growth Factor Rev"},{"issue":"1","key":"2330_CR49","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1186\/s12967-015-0507-z","volume":"13","author":"XY Zhao","year":"2015","unstructured":"Zhao XY, Wang YT, Mo XD, Zhao XS, Wang YZ, Chang YJ, et al. Higher frequency of regulatory T cells in granulocyte colony-stimulating factor (G-CSF)-primed bone marrow grafts compared with G-CSF-primed peripheral blood grafts. J Transl Med. 2015;13(1):145.","journal-title":"J Transl Med"},{"issue":"5","key":"2330_CR50","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1038\/nri2078","volume":"7","author":"O Leavy","year":"2007","unstructured":"Leavy O. Regulatory T cells in autoimmunity. Nat Rev Immunol. 2007;7(5):322\u20133.","journal-title":"Nat Rev Immunol"},{"key":"2330_CR51","doi-asserted-by":"publisher","first-page":"103379","DOI":"10.1016\/j.jaut.2025.103379","volume":"152","author":"MH Attrill","year":"2025","unstructured":"Attrill MH, Shinko D, Viveiros TM, Milighetti M, De Gruijter NM, Jebson B, et al. Treg fitness signatures as a biomarker for disease activity in Juvenile Idiopathic Arthritis. J Autoimmun. 2025;152:103379.","journal-title":"J Autoimmun"},{"key":"2330_CR52","doi-asserted-by":"crossref","unstructured":"Pesenacker AM, Chen V, Gillies J, Speake C, Marwaha AK, Sun AC et al. Treg gene signatures predict and measure type 1 diabetes trajectory. JCI Insight. 2019 Feb 7. Available from: http:\/\/insight.jci.org\/articles\/view\/123879","DOI":"10.1172\/jci.insight.123879"},{"issue":"1","key":"2330_CR53","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1038\/s41420-023-01765-8","volume":"9","author":"H Chen","year":"2023","unstructured":"Chen H, Wang X, Wang Y, Chang X. What happens to regulatory T cells in multiple myeloma. Cell Death Discov. 2023;9(1):468.","journal-title":"Cell Death Discov"},{"key":"2330_CR54","doi-asserted-by":"crossref","unstructured":"Pereira RS, Malvezi AD, Lovo-Martins MI, Lucchetti BFC, Santos JP, Tavares ER et al. Combination Therapy Using Benznidazole and Aspirin during the Acute Phase of Experimental Chagas Disease Prevents Cardiovascular Dysfunction and Decreases Typical Cardiac Lesions in the Chronic Phase. Antimicrob Agents Chemother. 2020 June 23;64(7):e00069-20.","DOI":"10.1128\/AAC.00069-20"},{"key":"2330_CR55","doi-asserted-by":"crossref","unstructured":"Carrillo I, Rabelo RAN, Barbosa C, Rates M, Fuentes-Retamal S, Gonz\u00e1lez-Herrera F et al. Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation in a murine model of early chronic Chagas disease. Santiago HDC, editor. PLoS Negl Trop Dis. 2021;15(11):e0009978.","DOI":"10.1371\/journal.pntd.0009978"},{"key":"2330_CR56","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2014\/580919","volume":"2014","author":"AD Malvezi","year":"2014","unstructured":"Malvezi AD, Da Silva RV, Panis C, Yamauchi LM, Lovo-Martins MI, Zanluqui NG, et al. Aspirin Modulates Innate Inflammatory Response and Inhibits the Entry of Trypanosoma cruzi in Mouse Peritoneal Macrophages. Mediat Inflamm. 2014;2014:1\u20139.","journal-title":"Mediat Inflamm"},{"issue":"5","key":"2330_CR57","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1021\/acsinfecdis.4c00125","volume":"10","author":"J Ruiz Luque","year":"2024","unstructured":"Ruiz Luque J, Cevey \u00c1C, Pieralisi AV, Poncini C, Erra D\u00edaz F, Azevedo Reis MV, et al. Fenofibrate Induces a Resolving Profile in Heart Macrophage Subsets and Attenuates Acute Chagas Myocarditis. ACS Infect Dis. 2024;10(5):1793\u2013807.","journal-title":"ACS Infect Dis"},{"key":"2330_CR58","doi-asserted-by":"crossref","unstructured":"Martins KSM, Tanaka DM, Fabricio CG, Barros Filho ACLD, Moreira HT, Louzada J\u00fanior P et al. Effects of pentoxifylline in patients with chronic Chagas cardiomyopathy: A randomized, double-blind, controlled pilot trial. Beatty N, editor. PLoS Negl Trop Dis. 2025;19(10):e0013555.","DOI":"10.1371\/journal.pntd.0013555"},{"issue":"1","key":"2330_CR59","doi-asserted-by":"publisher","first-page":"8449","DOI":"10.1038\/s41467-023-44297-6","volume":"14","author":"R Zayats","year":"2023","unstructured":"Zayats R, Mou Z, Yazdanpanah A, Gupta G, Lopez P, Nayar D, et al. Antigen recognition reinforces regulatory T cell mediated Leishmania major persistence. Nat Commun. 2023;14(1):8449.","journal-title":"Nat Commun"},{"issue":"10","key":"2330_CR60","doi-asserted-by":"publisher","first-page":"7214","DOI":"10.4049\/jimmunol.181.10.7214","volume":"181","author":"DR Herbert","year":"2008","unstructured":"Herbert DR, Orekov T, Perkins C, Finkelman FD. IL-10 and TGF-\u03b2 Redundantly Protect against Severe Liver Injury and Mortality during Acute Schistosomiasis. J Immunol. 2008;181(10):7214\u201320.","journal-title":"J Immunol"},{"key":"2330_CR61","doi-asserted-by":"crossref","unstructured":"Haque A, Best SE, Amante FH, Mustafah S, Desbarrieres L, De Labastida F et al. CD4\u2009+\u2009Natural Regulatory T Cells Prevent Experimental Cerebral Malaria via CTLA-4 When Expanded In Vivo. Riley EM, editor. PLoS Pathog. 2010;6(12):e1001221.","DOI":"10.1371\/journal.ppat.1001221"},{"key":"2330_CR62","doi-asserted-by":"crossref","unstructured":"Olszewski M, Li H, Hissong R, Goughenour K, Sinitsyna Y, Lintner M et al. Foxp3\u2009+\u2009Regulatory T Cells Restrain Th1 Response Shielding the Brain from Lethal Inflammatory Damage during Cryptococcal Meningoencephalitis [Internet]. In Review; 2025 [cited 2025 Dec 4]. Available from: https:\/\/www.researchsquare.com\/article\/rs-7142999\/v1","DOI":"10.21203\/rs.3.rs-7142999\/v1"},{"issue":"5","key":"2330_CR63","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1016\/j.immuni.2009.10.001","volume":"31","author":"G Oldenhove","year":"2009","unstructured":"Oldenhove G, Bouladoux N, Wohlfert EA, Hall JA, Chou D, Dos Santos L, et al. Decrease of Foxp3\u2009+\u2009Treg Cell Number and Acquisition of Effector Cell Phenotype during Lethal Infection. Immunity. 2009;31(5):772\u201386.","journal-title":"Immunity"},{"key":"2330_CR64","doi-asserted-by":"crossref","unstructured":"Serrano CJ, Lisb\u00f4a-Marques ME, Cerqueira-Silva T, Santos B, Oliveira LS, Ferreira Felix MA et al. I,. Cognitive impairment in Chagas disease patients in Brazil, 2007\u20132021: A cross-sectional study. Nakhasi HL, editor. PLoS Negl Trop Dis. 2025;19(5):e0012981.","DOI":"10.1371\/journal.pntd.0012981"},{"key":"2330_CR65","doi-asserted-by":"publisher","first-page":"e220287","DOI":"10.1590\/0074-02760220287","volume":"118","author":"J Lannes-Vieira","year":"2023","unstructured":"Lannes-Vieira J, Vilar-Pereira G, Barrios LC, Silva AA. Anxiety, depression, and memory loss in Chagas disease: a puzzle far beyond neuroinflammation to be unpicked and solved*. Mem Inst Oswaldo Cruz. 2023;118:e220287.","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"2330_CR66","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez FB, Savino W, P\u00e9rez AR. Brain-Thymus connections in Chagas Disease. Neuroimmunomodulation [Internet]. 2024 Apr 9 [cited 2025 Dec 4]; Available from: https:\/\/karger.com\/article\/doi\/10.1159\/00053822","DOI":"10.1159\/000538220"},{"issue":"2","key":"2330_CR67","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.pt.2024.12.005","volume":"41","author":"I de Brito Duval","year":"2025","unstructured":"de Brito Duval I, Cardozo ME, Souza JLN, de Medeiros Brito RM, Fujiwara RT, Bueno LL, Magalh\u00e3es LMD. Parasite infections: how inflammation alters brain function. Trends Parasitol. 2025;41(2):115\u201328. https:\/\/doi.org\/10.1016\/j.pt.2024.12.005.","journal-title":"Trends Parasitol"},{"key":"2330_CR68","doi-asserted-by":"publisher","first-page":"553","DOI":"10.3389\/fmicb.2018.00553","volume":"9","author":"BL Ferreira","year":"2018","unstructured":"Ferreira BL, Ferreira \u00c9R, De Brito MV, Salu BR, Oliva ML, Mortara RA, Orikaza CM. BALB\/c and C57BL\/6 mice cytokine responses to Trypanosoma cruzi infection are independent of parasite strain infectivity. Front Microbiol. 2018;9:553. https:\/\/doi.org\/10.3389\/fmicb.2018.00553.","journal-title":"Front Microbiol"},{"issue":"4","key":"2330_CR69","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1128\/iai.72.4.2350-2357.2004","volume":"72","author":"CR Marinho","year":"2004","unstructured":"Marinho CR, Bucci DZ, Dagli MLZ, Bastos KR, Grisotto MG, Sardinha LR, Alvarez JM. Pathology affects different organs in two mouse strains chronically infected by a Trypanosoma cruzi clone: a model for genetic studies of Chagas\u2019 disease. Infect Immun. 2004;72(4):2350\u20137.","journal-title":"Infect Immun"},{"issue":"3","key":"2330_CR70","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.jaci.2016.07.007","volume":"138","author":"RM Maizels","year":"2016","unstructured":"Maizels RM, McSorley HJ. Regulation of the host immune system by helminth parasites. J Allergy Clin Immunol. 2016;138(3):666\u201375. https:\/\/doi.org\/10.1016\/j.jaci.2016.07.007.","journal-title":"J Allergy Clin Immunol"},{"issue":"1","key":"2330_CR71","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1111\/imr.12164","volume":"259","author":"CM Finlay","year":"2014","unstructured":"Finlay CM, Walsh KP, Mills KH. Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases. Immunol Rev. 2014;259(1):206\u201330. https:\/\/doi.org\/10.1111\/imr.12164.","journal-title":"Immunol Rev"},{"key":"2330_CR72","doi-asserted-by":"publisher","first-page":"341","DOI":"10.3389\/fcimb.2017.00341","volume":"7","author":"N Ahmed","year":"2017","unstructured":"Ahmed N, French T, Rausch S, K\u00fchl A, Hemminger K, Dunay IR, Hartmann S. Toxoplasma co-infection prevents Th2 differentiation and leads to a helminth-specific Th1 response. Front Cell Infect Microbiol. 2017;7:341. https:\/\/doi.org\/10.3389\/fcimb.2017.00341.","journal-title":"Front Cell Infect Microbiol"},{"issue":"1","key":"2330_CR73","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1186\/s41936-025-00518-6","volume":"86","author":"MF Olaniyan","year":"2025","unstructured":"Olaniyan MF, Odegbemi OB, Babatunde ME, Iyare GI, Ochagu OR, Azeez MM. Immunological reprogramming during natural helminth\u2013protozoan coinfections: a cross-sectional population-based study in rural Nigeria. J Basic Appl Zool. 2025;86(1):106. https:\/\/doi.org\/10.1186\/s41936-025-00518-6.","journal-title":"J Basic Appl Zool"}],"container-title":["Inflammation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00011-026-02330-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00011-026-02330-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00011-026-02330-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:26:58Z","timestamp":1791826018000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00011-026-02330-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,12]]},"references-count":73,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2330"],"URL":"https:\/\/doi.org\/10.1007\/s00011-026-02330-6","relation":{},"ISSN":["1420-908X"],"issn-type":[{"value":"1420-908X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,12]]},"assertion":[{"value":"4 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 June 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 October 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The protocol for this systematic review was prospectively registered with PROSPERO (International Prospective Register of Systematic Reviews) under registration code: #CRD420251158158.","order":3,"name":"Ethics","label":"Protocol registration","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"234"}}