{"doi":"10.4049/jimmunol.178.7.4136","title":"Incomplete Depletion and Rapid Regeneration of Foxp3+ Regulatory T Cells Following Anti-CD25 Treatment in Malaria-Infected Mice","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>Investigation of the role of regulatory T cells (Treg) in model systems is facilitated by their depletion using anti-CD25 Abs, but there has been considerable debate about the effectiveness of this strategy. In this study, we have compared the depletion and repopulation of CD4+CD25+Foxp3+ Treg in uninfected and malaria-infected mice using 7D4 and/or PC61 anti-CD25 Abs. We find that numbers and percentages of CD25high cells, but not Foxp3+ cells, are transiently reduced after 7D4 treatment, whereas treatment with PC61 alone or in combination with 7D4 (7D4 plus PC61) reduces but does not eliminate Foxp3+ cells for up to 2 wk. Importantly, all protocols fail to eliminate significant populations of CD25−Foxp3+ or CD25lowFoxp3+ cells, which retain potent regulatory capacity. By adoptive transfer we show that repopulation of the spleen by CD25highFoxp3+ cells results from the re-expression of CD25 on peripheral populations of CD25−Foxp3+ but not from the conversion of peripheral Foxp3− cells. CD25highFoxp3+ repopulation occurs more rapidly in 7D4-treated mice than in 7D4 plus PC61-treated mice, reflecting ongoing clearance of emergent CD25+Foxp3+ cells by persistent PC61 Ab. However, in 7D4 plus PC61-treated mice undergoing acute malaria infection, repopulation of the spleen by CD25+Foxp3+ cells occurs extremely rapidly, with malaria infection driving proliferation and CD25 expression in peripheral CD4+CD25−Foxp3+ cells and/or conversion of CD4+CD25−Foxp3− cells. Finally, we reveal an essential role for IL-2 for the re-expression of CD25 by Foxp3+ cells after anti-CD25 treatment and observe that TGF-β is required, in the absence of CD25 and IL-2, to maintain splenic Foxp3+ cell numbers and a normal ratio of Treg:non-Treg cells.</jats:p>","journal":"The Journal of Immunology","year":2007,"id":588173,"datarank":8.043814896532123,"base_score":5.030437921392435,"endowment":5.030437921392435,"self_citation_contribution":0.7545656882088654,"citation_network_contribution":7.289249208323258,"self_endowment_contribution":0.7545656882088654,"citer_contribution":7.289249208323258,"corpus_percentile":null,"corpus_rank":null,"citation_count":152,"citer_count":142,"citers_with_citation_signal":123,"citers_with_endowment":123,"datacite_reuse_total":2,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1504626,"name":"Daniel G Blount","orcid":null,"position":1,"is_corresponding":false},{"id":1504627,"name":"J Brian de Souza","orcid":null,"position":2,"is_corresponding":false},{"id":1504628,"name":"Isabelle Suffia","orcid":null,"position":3,"is_corresponding":false},{"id":225267,"name":"Yasmine Belkaid","orcid":"0000-0001-9962-3571","position":4,"is_corresponding":false},{"id":1504629,"name":"Eleanor M Riley","orcid":null,"position":5,"is_corresponding":false},{"id":1504625,"name":"Kevin N Couper","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Incomplete Depletion and Rapid Regeneration of Foxp3+ Regulatory T Cells Following Anti-CD25 Treatment in Malaria-Infected Mice","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>Investigation of the role of regulatory T cells (Treg) in model systems is facilitated by their depletion using anti-CD25 Abs, but there has been considerable debate about the effectiveness of this strategy. In this study, we have compared the depletion and repopulation of CD4+CD25+Foxp3+ Treg in uninfected and malaria-infected mice using 7D4 and/or PC61 anti-CD25 Abs. We find that numbers and percentages of CD25high cells, but not Foxp3+ cells, are transiently reduced after 7D4 treatment, whereas treatment with PC61 alone or in combination with 7D4 (7D4 plus PC61) reduces but does not eliminate Foxp3+ cells for up to 2 wk. Importantly, all protocols fail to eliminate significant populations of CD25−Foxp3+ or CD25lowFoxp3+ cells, which retain potent regulatory capacity. By adoptive transfer we show that repopulation of the spleen by CD25highFoxp3+ cells results from the re-expression of CD25 on peripheral populations of CD25−Foxp3+ but not from the conversion of peripheral Foxp3− cells. CD25highFoxp3+ repopulation occurs more rapidly in 7D4-treated mice than in 7D4 plus PC61-treated mice, reflecting ongoing clearance of emergent CD25+Foxp3+ cells by persistent PC61 Ab. However, in 7D4 plus PC61-treated mice undergoing acute malaria infection, repopulation of the spleen by CD25+Foxp3+ cells occurs extremely rapidly, with malaria infection driving proliferation and CD25 expression in peripheral CD4+CD25−Foxp3+ cells and/or conversion of CD4+CD25−Foxp3− cells. Finally, we reveal an essential role for IL-2 for the re-expression of CD25 by Foxp3+ cells after anti-CD25 treatment and observe that TGF-β is required, in the absence of CD25 and IL-2, to maintain splenic Foxp3+ cell numbers and a normal ratio of Treg:non-Treg cells.</jats:p>","is_dataset_classified":null,"base_score":5.030437921392435,"endowment":5.030437921392435,"datacite_reuse_total":2,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"17371969","pmcid":"PMC2235934","openalex_id":"https://openalex.org/W1585751203","authors":[],"funders":[{"funder_name":"Wellcome Trust","grant_id":"074538","title":"Regulating cellular immune responses to malaria."}],"total_grants":1,"fwci":5.3936,"citation_percentile":0.96527641,"influential_citations":7,"citation_trend":[{"year":2012,"count":5},{"year":2013,"count":14},{"year":2014,"count":8},{"year":2015,"count":7},{"year":2016,"count":7},{"year":2017,"count":4},{"year":2018,"count":5},{"year":2019,"count":6},{"year":2020,"count":11},{"year":2021,"count":1},{"year":2022,"count":1},{"year":2023,"count":4},{"year":2024,"count":2},{"year":2025,"count":1}],"oa_status":"bronze","license":"OUP Standard Publication Reuse","oa_locations":[{"url":"https://journals.aai.org/jimmunol/article-pdf/178/7/4136/1240638/zim00707004136.pdf","host_type":"journal"},{"url":"https://journals.aai.org/jimmunol/article-pdf/178/7/4136/1240638/zim00707004136.pdf","host_type":"BRONZE"},{"url":"https://journals.aai.org/jimmunol/article-pdf/178/7/4136/1240638/zim00707004136.pdf","host_type":"publisher"},{"url":"https://academic.oup.com/jimmunol/article-pdf/178/7/4136/62657714/zim00707004136.pdf","host_type":"publisher"},{"url":"https://doi.org/10.4049/jimmunol.178.7.4136","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/17371969","host_type":"repository"},{"url":"https://research.manchester.ac.uk/en/publications/bcbac095-26a4-4f50-b27d-0a25fb7d4849","host_type":"repository"},{"url":"https://researchonline.lshtm.ac.uk/view/creators/iimmeril.html>;","host_type":"repository"},{"url":"http://discovery.ucl.ac.uk/120320/","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2235934","host_type":"repository"},{"url":"http://www.jimmunol.org/content/178/7/4136.full.pdf","host_type":""},{"url":"https://dx.doi.org/10.4049/jimmunol.178.7.4136","host_type":""}],"fields_of_study":["T-cell and B-cell Immunology","Immune Cell Function and Interaction","Immunotherapy and Immune Responses","Biology","Medicine","03 medical and health sciences","0302 clinical medicine","Animals","Antibodies, Monoclonal","CD4 Antigens","Disease Models, Animal","Forkhead Transcription Factors","Immunoglobulin G","Immunoglobulin M","Interleukin-2","Interleukin-2 Receptor alpha Subunit","Lymphocyte Depletion","Malaria","Mice","Mice, Inbred C57BL","Plasmodium yoelii","Regeneration","T-Lymphocytes, Regulatory","Transforming Growth Factor beta"],"mesh_terms":["Animals","Antibodies, Monoclonal","Disease Models, Animal","Immunoglobulin G","Immunoglobulin M","Interleukin-2","Lymphocyte Depletion","Malaria","Mice, Inbred C57BL","Plasmodium yoelii","Regeneration","CD4 Antigens","Transforming Growth Factor beta","T-Lymphocytes, Regulatory","Mice","Forkhead Transcription Factors","Interleukin-2 Receptor alpha Subunit"],"keywords":["FOXP3","IL-2 receptor","Spleen","Repopulation","Immunology","Biology","Adoptive cell transfer","Regulatory T cell","Cell biology","Immune system","T cell","Stem cell","Haematopoiesis","Interleukin-2 Receptor alpha Subunit","Antibodies, Monoclonal","Forkhead Transcription Factors","Plasmodium yoelii","T-Lymphocytes, Regulatory","Lymphocyte Depletion","Malaria","Mice, Inbred C57BL","Disease Models, Animal","Mice","Immunoglobulin M","Transforming Growth Factor beta","Immunoglobulin G","CD4 Antigens","Animals","Interleukin-2","Regeneration"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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