{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T17:45:07Z","timestamp":1775151907881,"version":"3.50.1"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2014,8,1]],"date-time":"2014-08-01T00:00:00Z","timestamp":1406851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A subset of human regulatory T cells (Tregs) secretes IL-17 and thus resembles Th17 effector cells. How IL-17+ Tregs differentiate from naive precursors remains unclear. In this study, we show that IL-17\u2013producing T cells can differentiate from CCR6+ naive T cell precursors in the presence of IL-2, IL-1\u03b2, TGF-\u03b2, and IL-23. CCR6+ naive T cells are present in adult peripheral and umbilical cord blood and in both conventional T naive and FOXP3+ naive Treg subsets. IL-17+ cells derived from CCR6+ naive Tregs (referred to as IL-17+ Tregs) express FOXP3 but not HELIOS, another Treg-associated transcription factor, and these cells display suppressor capacity and a surface phenotype resembling memory Tregs. Remarkably, the IL-17+ Treg compartment was preferentially reduced relative to the canonical Th17 and Treg compartments in a subset of HIV+ subjects, suggesting a specific perturbation of this subset during the course of disease. Our findings that CCR6+ naive precursors contain a predetermined reservoir to replenish IL-17\u2013secreting cells may have implications in balancing the Th17 and IL-17+ Treg compartments that are perturbed during HIV infection and potentially in other inflammatory diseases.<\/jats:p>","DOI":"10.4049\/jimmunol.1302936","type":"journal-article","created":{"date-parts":[[2014,6,24]],"date-time":"2014-06-24T08:09:20Z","timestamp":1403597360000},"page":"1047-1054","source":"Crossref","is-referenced-by-count":45,"title":["Differentiation of IL-17\u2013Producing Effector and Regulatory Human T Cells from Lineage-Committed Naive Precursors"],"prefix":"10.1093","volume":"193","author":[{"given":"Frances","family":"Mercer","sequence":"first","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine , New York, NY 10016"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alka","family":"Khaitan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, New York University School of Medicine , New York, NY 10016"},{"name":"Division of Infectious Diseases, New York University School of Medicine , New York, NY 10016"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Kozhaya","sequence":"additional","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine , New York, NY 10016"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith A","family":"Aberg","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, New York University School of Medicine , New York, NY 10016"},{"name":"Department of Medicine, New York University School of Medicine , New York, NY 10016"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derya","family":"Unutmaz","sequence":"additional","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine , New York, NY 10016"},{"name":"Department of Medicine, New York University School of Medicine , New York, NY 10016"},{"name":"Department of Pathology, New York University School of Medicine , New York, NY 10016"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,8,1]]},"reference":[{"key":"2025030707252721400_r1","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.immuni.2013.03.002","article-title":"Development and maintenance of regulatory T cells","volume":"38","author":"Ohkura","year":"2013","journal-title":"Immunity"},{"key":"2025030707252721400_r2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/978-1-4419-1599-3_4","article-title":"The biology of FoxP3: a key player in immune suppression during infections, autoimmune diseases and cancer","volume":"665","author":"Mercer","year":"2009","journal-title":"Adv. Exp. Med. Biol."},{"key":"2025030707252721400_r3","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1146\/annurev.immunol.25.022106.141623","article-title":"Regulatory T cells: mechanisms of differentiation and function","volume":"30","author":"Josefowicz","year":"2012","journal-title":"Annu. Rev. Immunol."},{"key":"2025030707252721400_r4","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1002\/eji.200939722","article-title":"Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity","volume":"39","author":"Sallusto","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"2025030707252721400_r5","doi-asserted-by":"crossref","first-page":"4430","DOI":"10.1182\/blood-2011-11-392324","article-title":"Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells","volume":"119","author":"Duhen","year":"2012","journal-title":"Blood"},{"key":"2025030707252721400_r6","doi-asserted-by":"crossref","first-page":"4793","DOI":"10.1073\/pnas.0900408106","article-title":"Identification of IL-17-producing FOXP3+ regulatory T cells in humans","volume":"106","author":"Voo","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030707252721400_r7","doi-asserted-by":"crossref","first-page":"164ra159","DOI":"10.1126\/scitranslmed.3004566","article-title":"Expression of ROR\u03b3t marks a pathogenic regulatory T cell subset in human colon cancer","volume":"4","author":"Blatner","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"2025030707252721400_r8","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1053\/j.gastro.2010.12.002","article-title":"Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases","volume":"140","author":"Hovhannisyan","year":"2011","journal-title":"Gastroenterology"},{"key":"2025030707252721400_r9","doi-asserted-by":"crossref","first-page":"4388","DOI":"10.4049\/jimmunol.1003251","article-title":"IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer","volume":"186","author":"Kryczek","year":"2011","journal-title":"J. Immunol."},{"key":"2025030707252721400_r10","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1016\/j.molimm.2010.02.001","article-title":"A role for the transcription factor Helios in human CD4+CD25+ regulatory T cells","volume":"47","author":"Getnet","year":"2010","journal-title":"Mol. Immunol."},{"key":"2025030707252721400_r11","doi-asserted-by":"crossref","first-page":"e34547","DOI":"10.1371\/journal.pone.0034547","article-title":"Phenotypic and functional properties of Helios+ regulatory T cells","volume":"7","author":"Zabransky","year":"2012","journal-title":"PLoS ONE"},{"key":"2025030707252721400_r12","doi-asserted-by":"crossref","first-page":"3433","DOI":"10.4049\/jimmunol.0904028","article-title":"Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells","volume":"184","author":"Thornton","year":"2010","journal-title":"J. Immunol."},{"key":"2025030707252721400_r13","doi-asserted-by":"crossref","first-page":"7129","DOI":"10.4049\/jimmunol.1090105","article-title":"Comment on \u201cExpression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells\u201d","volume":"185","author":"Verhagen","year":"2010","journal-title":"J. Immunol."},{"key":"2025030707252721400_r14","doi-asserted-by":"crossref","first-page":"e24226","DOI":"10.1371\/journal.pone.0024226","article-title":"Helios expression is a marker of T cell activation and proliferation","volume":"6","author":"Akimova","year":"2011","journal-title":"PLoS ONE"},{"key":"2025030707252721400_r15","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.4049\/jimmunol.1201379","article-title":"Helios+ and Helios\u2212 cells coexist within the natural FOXP3+ T regulatory cell subset in humans","volume":"190","author":"Himmel","year":"2013","journal-title":"J. Immunol."},{"key":"2025030707252721400_r16","doi-asserted-by":"crossref","first-page":"764","DOI":"10.4049\/jimmunol.180.2.764","article-title":"Naive precursors of human regulatory T cells require FoxP3 for suppression and are susceptible to HIV infection","volume":"180","author":"Antons","year":"2008","journal-title":"J. Immunol."},{"key":"2025030707252721400_r17","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1172\/JCI23963","article-title":"A peripheral circulating compartment of natural naive CD4 Tregs","volume":"115","author":"Valmori","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2025030707252721400_r18","doi-asserted-by":"crossref","first-page":"2830","DOI":"10.1182\/blood-2005-06-2403","article-title":"Persistence of naive CD45RA+ regulatory T cells in adult life","volume":"107","author":"Seddiki","year":"2006","journal-title":"Blood"},{"key":"2025030707252721400_r19","doi-asserted-by":"crossref","first-page":"13439","DOI":"10.1073\/pnas.0901965106","article-title":"Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells","volume":"106","author":"Wang","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030707252721400_r20","doi-asserted-by":"crossref","first-page":"2983","DOI":"10.1182\/blood-2007-06-094656","article-title":"Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-\u03b2 dependent but does not confer a regulatory phenotype","volume":"110","author":"Tran","year":"2007","journal-title":"Blood"},{"key":"2025030707252721400_r21","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1002\/eji.200838147","article-title":"Rethinking the molecular definition of regulatory T cells","volume":"38","author":"Hori","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"2025030707252721400_r22","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/nature06878","article-title":"TGF-\u03b2-induced Foxp3 inhibits TH17 cell differentiation by antagonizing ROR\u03b3t function","volume":"453","author":"Zhou","year":"2008","journal-title":"Nature"},{"key":"2025030707252721400_r23","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/nri2660","article-title":"Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective","volume":"9","author":"Weaver","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025030707252721400_r24","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1146\/annurev-pathol-011110-130318","article-title":"The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin","volume":"8","author":"Weaver","year":"2013","journal-title":"Annu. Rev. Pathol."},{"key":"2025030707252721400_r25","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.cell.2006.07.035","article-title":"The orphan nuclear receptor ROR\u03b3t directs the differentiation program of proinflammatory IL-17+ T helper cells","volume":"126","author":"Ivanov","year":"2006","journal-title":"Cell"},{"key":"2025030707252721400_r26","doi-asserted-by":"crossref","first-page":"2589","DOI":"10.4049\/jimmunol.178.4.2589","article-title":"IL-23 is critical in the induction but not in the effector phase of experimental autoimmune encephalomyelitis","volume":"178","author":"Thakker","year":"2007","journal-title":"J. Immunol."},{"key":"2025030707252721400_r27","doi-asserted-by":"crossref","first-page":"E198","DOI":"10.1371\/journal.pbio.0020198","article-title":"HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells","volume":"2","author":"Oswald-Richter","year":"2004","journal-title":"PLoS Biol."},{"key":"2025030707252721400_r28","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1084\/jem.20102516","article-title":"Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells","volume":"208","author":"Wan","year":"2011","journal-title":"J. Exp. Med."},{"key":"2025030707252721400_r29","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1093\/intimm\/dxl060","article-title":"Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis","volume":"18","author":"Sugimoto","year":"2006","journal-title":"Int. Immunol."},{"key":"2025030707252721400_r30","doi-asserted-by":"crossref","first-page":"8635","DOI":"10.1073\/pnas.0900621106","article-title":"Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineage-specific transcription factor ROR\u03b3t","volume":"106","author":"Ayyoub","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030707252721400_r31","doi-asserted-by":"crossref","first-page":"19402","DOI":"10.1073\/pnas.1008247107","article-title":"Human ROR\u03b3t+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage-specific polarizing factors","volume":"107","author":"Valmori","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030707252721400_r32","doi-asserted-by":"crossref","first-page":"e2705","DOI":"10.1371\/journal.pone.0002705","article-title":"Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression","volume":"3","author":"Wang","year":"2008","journal-title":"PLoS ONE"},{"key":"2025030707252721400_r33","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/eji.200738111","article-title":"The critical contribution of TGF-\u03b2 to the induction of Foxp3 expression and regulatory T cell function","volume":"38","author":"Shevach","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"2025030707252721400_r34","doi-asserted-by":"crossref","first-page":"5196","DOI":"10.4049\/jimmunol.1101742","article-title":"Ex vivo IL-1 receptor type I expression in human CD4+ T cells identifies an early intermediate in the differentiation of Th17 from FOXP3+ naive regulatory T cells","volume":"187","author":"Raffin","year":"2011","journal-title":"J. Immunol."},{"key":"2025030707252721400_r35","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1002\/eji.201243296","article-title":"CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner","volume":"43","author":"Afzali","year":"2013","journal-title":"Eur. J. Immunol."},{"key":"2025030707252721400_r36","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1182\/blood-2012-08-443473","article-title":"CD161 defines the subset of FoxP3+ T cells capable of producing proinflammatory cytokines","volume":"121","author":"Pesenacker","year":"2013","journal-title":"Blood"},{"key":"2025030707252721400_r37","doi-asserted-by":"crossref","first-page":"5125","DOI":"10.1182\/blood-2009-01-199950","article-title":"Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I\/II (CD121a\/CD121b) on activated human FOXP3+ regulatory T cells allows for their purification from expansion cultures","volume":"113","author":"Tran","year":"2009","journal-title":"Blood"},{"key":"2025030707252721400_r38","doi-asserted-by":"crossref","first-page":"e8639","DOI":"10.1371\/journal.pone.0008639","article-title":"Expression and function of TNF and IL-1 receptors on human regulatory T cells","volume":"5","author":"Mercer","year":"2010","journal-title":"PLoS ONE"},{"key":"2025030707252721400_r39","first-page":"114","article-title":"HIV disease progression: immune activation, microbes, and a leaky gut","volume":"15","author":"Douek","year":"2007","journal-title":"Top. HIV Med."},{"key":"2025030707252721400_r40","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1097\/COH.0b013e328335c0c1","article-title":"Th17 and regulatory T cells: implications for AIDS pathogenesis","volume":"5","author":"Kanwar","year":"2010","journal-title":"Curr. Opin. HIV AIDS"},{"key":"2025030707252721400_r41","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/ni1496","article-title":"Interleukins 1\u03b2 and 6 but not transforming growth factor-\u03b2 are essential for the differentiation of interleukin 17-producing human T helper cells","volume":"8","author":"Acosta-Rodriguez","year":"2007","journal-title":"Nat. Immunol."},{"key":"2025030707252721400_r42","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/ni.1610","article-title":"The differentiation of human TH-17 cells requires transforming growth factor-\u03b2 and induction of the nuclear receptor ROR\u03b3t","volume":"9","author":"Manel","year":"2008","journal-title":"Nat. Immunol."},{"key":"2025030707252721400_r43","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/nature10957","article-title":"Pathogen-induced human TH17 cells produce IFN-\u03b3 or IL-10 and are regulated by IL-1\u03b2","volume":"484","author":"Zielinski","year":"2012","journal-title":"Nature"},{"key":"2025030707252721400_r44","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1038\/ni.1783","article-title":"Thymic self-reactivity selects natural interleukin 17-producing T cells that can regulate peripheral inflammation","volume":"10","author":"Marks","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025030707252721400_r45","doi-asserted-by":"crossref","first-page":"4240","DOI":"10.1182\/blood-2008-10-183251","article-title":"IL-17-producing human peripheral regulatory T cells retain suppressive function","volume":"113","author":"Beriou","year":"2009","journal-title":"Blood"},{"key":"2025030707252721400_r46","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.clim.2003.09.013","article-title":"Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice","volume":"110","author":"Ogawa","year":"2004","journal-title":"Clin. Immunol."},{"key":"2025030707252721400_r47","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1126\/science.1214935","article-title":"Disease tolerance as a defense strategy","volume":"335","author":"Medzhitov","year":"2012","journal-title":"Science"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/193\/3\/1047\/62228767\/1302936.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/193\/3\/1047\/62228767\/1302936.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:50:25Z","timestamp":1741333825000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/193\/3\/1047\/7960250"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8,1]]},"references-count":47,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2014,8,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1302936","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,8]]},"published":{"date-parts":[[2014,8,1]]}}}