{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:37:32Z","timestamp":1790905052918,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007270","name":"University of Michigan","doi-asserted-by":"publisher","award":["R01AI141673"],"award-info":[{"award-number":["R01AI141673"]}],"id":[{"id":"10.13039\/100007270","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunol Cell Biol"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Neonatal CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells have reduced or delayed T\u2010cell receptor (TCR) signaling responses compared with adult cells, but the mechanisms underlying this are poorly understood. This study tested the hypothesis that human neonatal na\u00efve CD4\n                    <jats:sup>+<\/jats:sup>\n                    TCR signaling and activation deficits are related to differences in H3K4me3 patterning and chromatin accessibility. Following initiation of TCR signaling using anti\u2010CD3\/anti\u2010CD28 beads, adult na\u00efve CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells demonstrated increased CD69, phospho\u2010CD3\u03b5 and interleukin (IL)\u20102, tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1), interferon\u2010\u03b3 and IL\u201017A compared with neonatal cells. By contrast, following TCR\u2010independent activation using phorbol myristate acetate (PMA)\/ionomycin, neonatal cells demonstrated increased expression of CD69, IL\u20102 and TNF\u2010\u03b1 and equivalent phospho\u2010ERK compared with adult cells. H3K4me3 chromatin immunoprecipitation\u2010sequencing (ChIP\u2010seq) and assay for transposase\u2010accessible chromatin with high\u2010throughput sequencing (ATAC\u2010seq) were performed on separate cohorts of na\u00efve CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells from term neonates and adults, and RNA\u2010seq data from neonatal and adult na\u00efve CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells were obtained from the Blueprint Consortium. Adult cells demonstrated overall increased chromatin accessibility and a higher proportion of H3K4me3 sites associated with open chromatin and active gene transcription compared with neonatal cells. Adult cells demonstrated increased mRNA expression of the TCR\u2010associated genes\n                    <jats:italic>FYN<\/jats:italic>\n                    ,\n                    <jats:italic>ITK<\/jats:italic>\n                    ,\n                    <jats:italic>CD4<\/jats:italic>\n                    ,\n                    <jats:italic>LCK<\/jats:italic>\n                    and\n                    <jats:italic>LAT<\/jats:italic>\n                    , which was associated with increased H3K4me3 at the\n                    <jats:italic>FYN<\/jats:italic>\n                    and\n                    <jats:italic>ITK<\/jats:italic>\n                    gene loci and increased chromatin accessibility at the\n                    <jats:italic>CD4<\/jats:italic>\n                    ,\n                    <jats:italic>LCK<\/jats:italic>\n                    and\n                    <jats:italic>LAT<\/jats:italic>\n                    loci. These findings indicate that neonatal TCR\u2010dependent defects in activation are epigenetically regulated and provide a potentially targetable mechanism to enhance neonatal CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell responses.\n                  <\/jats:p>","DOI":"10.1111\/imcb.12561","type":"journal-article","created":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T12:37:57Z","timestamp":1653395877000},"page":"562-579","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Differences in\n                    <scp>H3K4me3<\/scp>\n                    and chromatin accessibility contribute to altered T\u2010cell receptor signaling in neonatal na\u00efve\n                    <scp>CD4<\/scp>\n                    T cells"],"prefix":"10.1111","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0245-946X","authenticated-orcid":false,"given":"Jennifer R","family":"Bermick","sequence":"first","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics University of Iowa  Iowa City IA USA"},{"name":"Division of Neonatal\u2010Perinatal Medicine, Department of Pediatrics Michigan Medicine  Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Issuree","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Iowa  Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"denDekker","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery Michigan Medicine  Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery Michigan Medicine  Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Santillan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Iowa  Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Kunkel","sequence":"additional","affiliation":[{"name":"Department of Pathology Michigan Medicine  Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Lukacs","sequence":"additional","affiliation":[{"name":"Department of Pathology Michigan Medicine  Ann Arbor MI USA"},{"name":"Mary H. 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