{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:11:45Z","timestamp":1790223105525,"version":"4.1.0"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"47","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI072073"],"award-info":[{"award-number":["AI072073"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000070","name":"HHS | NIH | National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"publisher","award":["EB029455"],"award-info":[{"award-number":["EB029455"]}],"id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL170146"],"award-info":[{"award-number":["HL170146"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007028","name":"Leona M. and Harry B. Helmsley Charitable Trust","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100007028","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009576","name":"Kenneth Rainin Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100009576","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM007753"],"award-info":[{"award-number":["GM007753"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM144273"],"award-info":[{"award-number":["GM144273"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008035","name":"Harvard | Harvard Stem Cell Institute","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100008035","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,11,25]]},"abstract":"<jats:p>Interleukin-2 (IL2) is the key trophic factor for T regulatory (Treg) cells, controlling their differentiation and homeostasis. To understand how temporally regulated responses to IL2 unfold in Tregs, we performed fine time-course analyses, at population and single-cell levels, of changes in chromatin architecture and mRNAs induced by IL2 in Tregs in vivo. The data revealed responses that were largely uniform in rTreg, but diverse among aTregs, matching different STAT5 signal transduction efficiency. Individual Tregs displayed divergences in the preponderance of changes that may be attributed to STAT1 or STAT5 signal transduction downstream of IL2. Chromatin analysis identified an evolving implication of transcription factors that accounted for the waves of responsive genes. Covalent cytokine\/Ab complexes that preferentially trigger high- (heterotrimer) or low-affinity (heterodimer) IL2 receptors activated the same signatures, yet with strong quantitative variations, especially in NK cells. Thus, IL2 is not a monolithic activator for Tregs, but a variegated sculptor of Treg identity.<\/jats:p>","DOI":"10.1073\/pnas.2518991122","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T16:21:33Z","timestamp":1763655693000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Dynamics and variegation in the Treg response to Interleukin-2"],"prefix":"10.1073","volume":"122","author":[{"given":"Kumba","family":"Seddu","sequence":"first","affiliation":[{"name":"Department of Immunology, Harvard Medical School","place":["Boston"]},{"name":"Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitavjeet","family":"Chowdhary","sequence":"additional","affiliation":[{"name":"Department of Immunology, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"Henderson","sequence":"additional","affiliation":[{"name":"Department of Immunology, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakub","family":"Tomala","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, Johns Hopkins University","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odhran","family":"Casey","sequence":"additional","affiliation":[{"name":"Department of Immunology, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Immunology, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Mathis","sequence":"additional","affiliation":[{"name":"Department of Immunology, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8187-3732","authenticated-orcid":false,"given":"Jamie B.","family":"Spangler","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health","place":["Baltimore"]},{"name":"Department of Chemical and Biomolecular Engineering, Johns Hopkins University","place":["Baltimore"]},{"name":"Department of Biomedical Engineering, Johns Hopkins University School of Medicine","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Benoist","sequence":"additional","affiliation":[{"name":"Department of Immunology, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042617-053352"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0046-y"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.02.001"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.120.6.2027"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6427923"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1263"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041982"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.25.022106.141623"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-095948"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1002006107"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2012.11.002"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00333"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0051-0"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00519-w"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2006"},{"key":"e_1_3_4_16_2","first-page":"eabj9836","article-title":"Foxp3 associates with enhancer-promoter loops to regulate Treg-specific gene expression","volume":"7","author":"Ramirez R. N.","year":"2022","unstructured":"R. N. Ramirez , Foxp3 associates with enhancer-promoter loops to regulate Treg-specific gene expression. Sci. Immunol. 7, eabj9836 (2022).","journal-title":"Sci. Immunol."},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2411301121"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.11.022"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190993"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3156"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.03.011"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.05.028"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41435-023-00221-y"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00680-w"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.07.031"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.17.7779"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.07.022"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.148.8.2417"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80388-X"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.2217\/imt.14.84"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20222052"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01179-1"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06816-9"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.07.016"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20241207"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1122927"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101289"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.173469"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111478"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-00927-2"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3004"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.12.032"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.05.014"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00836-7"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80097-7"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.1.280"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2022.100166"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3192"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.111248"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131142"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.07.006"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13577"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.03.005"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0161507"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04753"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2016.84"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-021-01282-5"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4401"},{"key":"e_1_3_4_60_2","doi-asserted-by":"crossref","unstructured":"K. Seddu Data from \u201cDynamics and variegation in the Treg response to Interleukin-2.\u201d https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE297025. Deposited 13 May 2025.","DOI":"10.1073\/pnas.2518991122"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2518991122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:56:55Z","timestamp":1763686615000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2518991122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,20]]},"references-count":60,"journal-issue":{"issue":"47","published-print":{"date-parts":[[2025,11,25]]}},"alternative-id":["10.1073\/pnas.2518991122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2518991122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,20]]},"assertion":[{"value":"2025-07-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2518991122"}}