{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:00:18Z","timestamp":1789761618166,"version":"4.0.1"},"reference-count":43,"publisher":"American Society for Clinical Investigation","issue":"22","funder":[{"name":"NIH and Rheumatology Research Foundation","award":["see comments"],"award-info":[{"award-number":["see comments"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,14]]},"abstract":"<jats:p>Dysregulated citrullination, a unique form of posttranslational modification catalyzed by the peptidylarginine deiminases (PADs), has been observed in several human diseases, including rheumatoid arthritis. However, the physiological roles of PADs in the immune system are still poorly understood. Here, we report that global inhibition of citrullination enhances the differentiation of type 2 helper T (Th2) cells but attenuates the differentiation of Th17 cells, thereby increasing the susceptibility to allergic airway inflammation. This effect on Th cells is due to inhibition of PAD2 but not PAD4. Mechanistically, PAD2 directly citrullinates GATA3 and ROR\u03b3t, 2 key transcription factors determining the fate of differentiating Th cells. Citrullination of R330 of GATA3 weakens its DNA binding ability, whereas citrullination of 4 arginine residues of ROR\u03b3t strengthens its DNA binding. Finally, PAD2-deficient mice also display altered Th2\/Th17 immune response and heightened sensitivity to allergic airway inflammation. Thus, our data highlight the potential and caveat of PAD2 as a therapeutic target of Th cell\u2013mediated diseases.<\/jats:p>","DOI":"10.1172\/jci.insight.129687","type":"journal-article","created":{"date-parts":[[2019,11,13]],"date-time":"2019-11-13T11:01:11Z","timestamp":1573642871000},"source":"Crossref","is-referenced-by-count":46,"title":["Reciprocal regulation of Th2 and Th17 cells by PAD2-mediated citrullination"],"prefix":"10.1172","volume":"4","author":[{"given":"Bo","family":"Sun","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Hsin","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ari","family":"Salinger","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly","family":"Tomita","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4113-8669","authenticated-orcid":true,"given":"Mandar","family":"Bawadekar","sequence":"additional","affiliation":[{"name":"Department of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlyn L.","family":"Holmes","sequence":"additional","affiliation":[{"name":"Department of Medicine and"},{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam A.","family":"Shelef","sequence":"additional","affiliation":[{"name":"Department of Medicine and"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eranthie","family":"Weerapana","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Boston College, Chestnut Hill, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3906-0345","authenticated-orcid":true,"given":"I-Cheng","family":"Ho","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2019,11,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2174\/1389450116666150202160954"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2007.05.005"},{"key":"B3","article-title":"Peptidylarginine deiminase 1-catalyzed histone citrullination is essential for early embryo development","volume":"6","author":"Zhang","year":"2016","journal-title":"Sci Rep"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100239"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-011-0193-7"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2009.00853.x"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/art.34595"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2007.075192"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/art.39215"},{"issue":"17","key":"B10","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.90045","article-title":"A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22","volume":"1","author":"Chang","year":"2016","journal-title":"JCI Insight"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12037"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.4.2491"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.621524"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1084\/jem.2013237805062015c"},{"key":"B15","article-title":"Reciprocal regulation of ROR\u03b3t acetylation and function by p300 and HDAC1","volume":"5","author":"Wu","year":"2015","journal-title":"Sci Rep"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00274"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1735"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.5b00438"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2018.03.002"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aal3062"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/glia.10039"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.06.072"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nature12942"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1501257"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00254.2016"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.10.016"},{"key":"B27","doi-asserted-by":"crossref","DOI":"10.1038\/srep26430","article-title":"Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses","volume":"6","author":"Kawalkowska","year":"2016","journal-title":"Sci Rep"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/all.12651"},{"issue":"23","key":"B29","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.124729","article-title":"Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7-dependent lupus","volume":"3","author":"Liu","year":"2018","journal-title":"JCI Insight"},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.1038\/srep13041","article-title":"Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model","volume":"5","author":"Seri","year":"2015","journal-title":"Sci Rep"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/cne.21055"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201141871"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2017.01.006"},{"key":"B34","doi-asserted-by":"crossref","DOI":"10.1038\/s41541-016-0001-5","article-title":"Neutrophil swarming and extracellular trap formation play a significant role in Alum adjuvant activity","volume":"2","author":"Stephen","year":"2017","journal-title":"NPJ Vaccines"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aao4747"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.10.012"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.2174\/156802612799436641"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1203280109"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203363"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.8.4414"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405764200"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.06.038"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2016.00078"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/129687\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:21:26Z","timestamp":1779193286000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/129687"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,14]]},"references-count":43,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2019,11,14]]},"published-print":{"date-parts":[[2019,11,14]]}},"alternative-id":["10.1172\/jci.insight.129687"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.129687","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,14]]},"article-number":"e129687"}}