{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T11:53:18Z","timestamp":1792756398441,"version":"4.5.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2016,1,1]],"date-time":"2016-01-01T00:00:00Z","timestamp":1451606400000},"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":[[2016,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A subpopulation (60\u201370%) of Foxp3+ regulatory T cells (Tregs) in both mouse and man expresses the transcription factor Helios, but its role in Treg function is still unknown. We generated Treg-specific Helios-deficient mice to examine the function of Helios in Tregs. We show that the selective deletion of Helios in Tregs leads to slow, progressive systemic immune activation, hypergammaglobulinemia, and enhanced germinal center formation in the absence of organ-specific autoimmunity. Helios-deficient Treg suppressor function was normal in vitro, as well as in an in vivo inflammatory bowel disease model. However, Helios-deficient Tregs failed to control the expansion of pathogenic T cells derived from scurfy mice, failed to mediate T follicular regulatory cell function, and failed to control both T follicular helper cell and Th1 effector cell responses. In competitive settings, Helios-deficient Tregs, particularly effector Tregs, were at a disadvantage, indicating that Helios regulates effector Treg fitness. Thus, we demonstrate that Helios controls certain aspects of Treg-suppressive function, differentiation, and survival.<\/jats:p>","DOI":"10.4049\/jimmunol.1501704","type":"journal-article","created":{"date-parts":[[2015,11,19]],"date-time":"2015-11-19T03:33:17Z","timestamp":1447903997000},"page":"144-155","source":"Crossref","is-referenced-by-count":168,"title":["Helios Controls a Limited Subset of Regulatory T Cell Functions"],"prefix":"10.1093","volume":"196","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1058-1676","authenticated-orcid":false,"given":"Mathew","family":"Sebastian","sequence":"first","affiliation":[{"name":"Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4463-5801","authenticated-orcid":false,"given":"Maria","family":"Lopez-Ocasio","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amina","family":"Metidji","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadiye Amcaoglu","family":"Rieder","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan M","family":"Shevach","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4175-4154","authenticated-orcid":false,"given":"Angela M","family":"Thornton","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,1,1]]},"reference":[{"key":"2025030702112396500_r1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0092-8674(94)90407-3","article-title":"The Ikaros gene is required for the development of all lymphoid lineages","volume":"79","author":"Georgopoulos","year":"1994","journal-title":"Cell"},{"key":"2025030702112396500_r2","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S1074-7613(00)80269-1","article-title":"Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation","volume":"5","author":"Wang","year":"1996","journal-title":"Immunity"},{"key":"2025030702112396500_r3","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/S1074-7613(00)80637-8","article-title":"Aiolos regulates B cell activation and maturation to effector state","volume":"9","author":"Wang","year":"1998","journal-title":"Immunity"},{"key":"2025030702112396500_r4","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/ni.2363","article-title":"Aiolos promotes TH17 differentiation by directly silencing Il2 expression","volume":"13","author":"Quintana","year":"2012","journal-title":"Nat. Immunol."},{"key":"2025030702112396500_r5","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.4049\/jimmunol.0901407","article-title":"Helios deficiency has minimal impact on T cell development and function","volume":"183","author":"Cai","year":"2009","journal-title":"J. Immunol."},{"key":"2025030702112396500_r6","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/S0960-9822(98)70202-7","article-title":"Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors","volume":"8","author":"Kelley","year":"1998","journal-title":"Curr. Biol."},{"key":"2025030702112396500_r7","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1101\/gad.12.6.782","article-title":"Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin","volume":"12","author":"Hahm","year":"1998","journal-title":"Genes Dev."},{"key":"2025030702112396500_r8","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":"2025030702112396500_r9","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1084\/jem.20031562","article-title":"Developmental stage, phenotype, and migration distinguish naive- and effector\/memory-like CD4+ regulatory T cells","volume":"199","author":"Huehn","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025030702112396500_r10","doi-asserted-by":"crossref","first-page":"301","DOI":"10.4049\/jimmunol.178.1.301","article-title":"FoxP3+ T cells undergo conventional first switch to lymphoid tissue homing receptors in thymus but accelerated second switch to nonlymphoid tissue homing receptors in secondary lymphoid tissues","volume":"178","author":"Lee","year":"2007","journal-title":"J. Immunol."},{"key":"2025030702112396500_r11","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1084\/jem.20131142","article-title":"CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets","volume":"211","author":"Smigiel","year":"2014","journal-title":"J. Exp. Med."},{"key":"2025030702112396500_r12","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/ni.1731","article-title":"The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation","volume":"10","author":"Koch","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025030702112396500_r13","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/nature07674","article-title":"Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses","volume":"458","author":"Zheng","year":"2009","journal-title":"Nature"},{"key":"2025030702112396500_r14","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1126\/science.1172702","article-title":"CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner","volume":"326","author":"Chaudhry","year":"2009","journal-title":"Science"},{"key":"2025030702112396500_r15","doi-asserted-by":"crossref","first-page":"4503","DOI":"10.1172\/JCI57456","article-title":"GATA3 controls Foxp3\u207a regulatory T cell fate during inflammation in mice","volume":"121","author":"Wohlfert","year":"2011","journal-title":"J. Clin. Invest."},{"key":"2025030702112396500_r16","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/ni.3053","article-title":"Dynamic expression of transcription factors T-bet and GATA-3 by regulatory T cells maintains immunotolerance","volume":"16","author":"Yu","year":"2015","journal-title":"Nat. Immunol."},{"key":"2025030702112396500_r17","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1038\/nm.2426","article-title":"Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions","volume":"17","author":"Chung","year":"2011","journal-title":"Nat. Med."},{"key":"2025030702112396500_r18","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1038\/nm.2425","article-title":"Foxp3+ follicular regulatory T cells control the germinal center response","volume":"17","author":"Linterman","year":"2011","journal-title":"Nat. Med."},{"key":"2025030702112396500_r19","doi-asserted-by":"crossref","first-page":"4553","DOI":"10.4049\/jimmunol.1101328","article-title":"Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells","volume":"187","author":"Wollenberg","year":"2011","journal-title":"J. Immunol."},{"key":"2025030702112396500_r20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/imm.12393","article-title":"The transcriptional repressor Bcl6 controls the stability of regulatory T cells by intrinsic and extrinsic pathways","volume":"145","author":"Sawant","year":"2015","journal-title":"Immunology"},{"key":"2025030702112396500_r21","doi-asserted-by":"crossref","first-page":"4759","DOI":"10.4049\/jimmunol.1201794","article-title":"Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing Gata3 function","volume":"189","author":"Sawant","year":"2012","journal-title":"J. Immunol."},{"key":"2025030702112396500_r22","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1126\/science.1198469","article-title":"Induction of colonic regulatory T cells by indigenous Clostridium species","volume":"331","author":"Atarashi","year":"2011","journal-title":"Science"},{"key":"2025030702112396500_r23","doi-asserted-by":"crossref","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":"2025030702112396500_r24","doi-asserted-by":"publisher","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":"2025030702112396500_r25","doi-asserted-by":"crossref","first-page":"976","DOI":"10.4049\/jimmunol.1102964","article-title":"Expression of Helios in peripherally induced Foxp3+ regulatory T cells","volume":"188","author":"Gottschalk","year":"2012","journal-title":"J. Immunol."},{"key":"2025030702112396500_r26","doi-asserted-by":"crossref","first-page":"3784","DOI":"10.4049\/jimmunol.1402960","article-title":"Distinct modes of antigen presentation promote the formation, differentiation, and activity of foxp3+ regulatory T cells in vivo","volume":"194","author":"Weissler","year":"2015","journal-title":"J. Immunol."},{"key":"2025030702112396500_r27","doi-asserted-by":"publisher","first-page":"e20731","DOI":"10.1371\/journal.pone.0020731","article-title":"Helios is associated with CD4 T cells differentiating to T helper 2 and follicular helper T cells in vivo independently of Foxp3 expression","volume":"6","author":"Serre","year":"2011","journal-title":"PLoS One"},{"key":"2025030702112396500_r28","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.immuni.2008.02.017","article-title":"Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces","volume":"28","author":"Rubtsov","year":"2008","journal-title":"Immunity"},{"key":"2025030702112396500_r29","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/icb.2014.108","article-title":"Promiscuous Foxp3-cre activity reveals a differential requirement for CD28 in Foxp3+ and Foxp3\u2212 T cells","volume":"93","author":"Franckaert","year":"2015","journal-title":"Immunol. Cell Biol."},{"key":"2025030702112396500_r30","doi-asserted-by":"publisher","first-page":"e38","DOI":"10.1371\/journal.pbio.0050038","article-title":"Epigenetic control of the foxp3 locus in regulatory T cells","volume":"5","author":"Floess","year":"2007","journal-title":"PLoS Biol."},{"key":"2025030702112396500_r31","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/nri3605","article-title":"Homeostatic control of regulatory T cell diversity","volume":"14","author":"Liston","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"2025030702112396500_r32","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/imr.12170","article-title":"Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation","volume":"259","author":"Smigiel","year":"2014","journal-title":"Immunol. Rev."},{"key":"2025030702112396500_r33","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/ni.2649","article-title":"Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3\u207a regulatory T cells","volume":"14","author":"Pierson","year":"2013","journal-title":"Nat. Immunol."},{"key":"2025030702112396500_r34","doi-asserted-by":"crossref","first-page":"3632","DOI":"10.1002\/eji.201444750","article-title":"Fluorochrome-based definition of naturally occurring Foxp3(+) regulatory T cells of intra- and extrathymic origin","volume":"44","author":"Petzold","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"2025030702112396500_r35","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1084\/jem.20131019","article-title":"TRAF3 regulates the effector function of regulatory T cells and humoral immune responses","volume":"211","author":"Chang","year":"2014","journal-title":"J. Exp. Med."},{"key":"2025030702112396500_r36","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.immuni.2014.05.010","article-title":"Macrophages, immunity, and metabolic disease","volume":"41","author":"McNelis","year":"2014","journal-title":"Immunity"},{"key":"2025030702112396500_r37","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1038\/nm.2002","article-title":"Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters","volume":"15","author":"Feuerer","year":"2009","journal-title":"Nat. Med."},{"key":"2025030702112396500_r38","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nature11132","article-title":"PPAR-\u03b3 is a major driver of the accumulation and phenotype of adipose tissue Treg cells","volume":"486","author":"Cipolletta","year":"2012","journal-title":"Nature"},{"key":"2025030702112396500_r39","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.4049\/jimmunol.1200792","article-title":"Helios induces epigenetic silencing of IL2 gene expression in regulatory T cells","volume":"190","author":"Baine","year":"2013","journal-title":"J. Immunol."},{"key":"2025030702112396500_r40","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1038\/ni.2402","article-title":"Transcription factor Foxp3 and its protein partners form a complex regulatory network","volume":"13","author":"Rudra","year":"2012","journal-title":"Nat. Immunol."},{"key":"2025030702112396500_r41","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1038\/ni.2420","article-title":"A multiply redundant genetic switch \u2018locks in\u2019 the transcriptional signature of regulatory T cells","volume":"13","author":"Fu","year":"2012","journal-title":"Nat. Immunol."},{"key":"2025030702112396500_r42","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nri2343","article-title":"How regulatory T cells work","volume":"8","author":"Vignali","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2025030702112396500_r43","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1111\/imr.12160","article-title":"tTregs, pTregs, and iTregs: similarities and differences","volume":"259","author":"Shevach","year":"2014","journal-title":"Immunol. Rev."},{"key":"2025030702112396500_r44","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1126\/science.aad0616","article-title":"Stable inhibitory activity of regulatory T cells requires the transcription factor Helios","volume":"350","author":"Kim","year":"2015","journal-title":"Science"},{"key":"2025030702112396500_r45","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1126\/science.aaa7017","article-title":"Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance","volume":"348","author":"Yang","year":"2015","journal-title":"Science"},{"key":"2025030702112396500_r46","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.4049\/jimmunol.1003224","article-title":"CD4+FOXP3+ T regulatory cells in human autoimmunity: more than a numbers game","volume":"187","author":"Long","year":"2011","journal-title":"J. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/196\/1\/144\/62254658\/1501704.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/196\/1\/144\/62254658\/1501704.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T02:13:54Z","timestamp":1741313634000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/196\/1\/144\/7973613"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,1]]},"references-count":46,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2016,1,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1501704","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,1]]},"published":{"date-parts":[[2016,1,1]]}}}