{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:53:39Z","timestamp":1790952819972,"version":"4.1.0"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2015,10,1]],"date-time":"2015-10-01T00:00:00Z","timestamp":1443657600000},"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":[[2015,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The transcription factor IFN regulatory factor (IRF)4 was shown to play a crucial role in the protective CD8+ T cell response; however, regulation of IRF4 expression in CD8+ T cells remains unclear. In this article, we report a critical role for Nr4a1 in regulating the expansion, differentiation, and function of CD8+ T cells through direct transcriptional repression of Irf4. Without Nr4a1, the regulation of IRF4 is lost, driving an increase in Irf4 expression and, in turn, resulting in a faster rate of CD8 T cell proliferation and expansion. Nr4a1-deficient mice show increases in CD8 T cell effector responses with improved clearance of Listeria monocytogenes. Our data support a novel and critical role for Nr4a1 in the regulation of CD8+ T cell expansion and effector function through transcriptional repression of Irf4.<\/jats:p>","DOI":"10.4049\/jimmunol.1403027","type":"journal-article","created":{"date-parts":[[2015,9,12]],"date-time":"2015-09-12T02:14:11Z","timestamp":1442024051000},"page":"3515-3519","source":"Crossref","is-referenced-by-count":50,"title":["Cutting Edge: The Orphan Nuclear Receptor Nr4a1 Regulates CD8+ T Cell Expansion and Effector Function through Direct Repression of Irf4"],"prefix":"10.1093","volume":"195","author":[{"given":"Heba N","family":"Nowyhed","sequence":"first","affiliation":[{"name":"Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tridu R","family":"Huynh","sequence":"additional","affiliation":[{"name":"Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham D","family":"Thomas","sequence":"additional","affiliation":[{"name":"Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Blatchley","sequence":"additional","affiliation":[{"name":"Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine C","family":"Hedrick","sequence":"additional","affiliation":[{"name":"Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,10,15]]},"reference":[{"key":"2025030704171638600_r1","doi-asserted-by":"crossref","first-page":"S57","DOI":"10.1016\/S0092-8674(02)00710-9","article-title":"Nuclear hormone receptors in T lymphocytes","volume":"109","author":"Winoto","year":"2002","journal-title":"Cell"},{"key":"2025030704171638600_r2","first-page":"533","article-title":"NR4A1, 2, 3--an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis","volume":"21","author":"Li","year":"2006","journal-title":"Histol. Histopathol."},{"key":"2025030704171638600_r3","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/367281a0","article-title":"Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77","volume":"367","author":"Liu","year":"1994","journal-title":"Nature"},{"key":"2025030704171638600_r4","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/ni.2520","article-title":"Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis","volume":"14","author":"Sekiya","year":"2013","journal-title":"Nat. Immunol."},{"key":"2025030704171638600_r5","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1600-065X.1994.tb00894.x","article-title":"Identification of genes induced during apoptosis in T lymphocytes","volume":"142","author":"Osborne","year":"1994","journal-title":"Immunol. Rev."},{"key":"2025030704171638600_r6","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1084\/jem.20110308","article-title":"T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse","volume":"208","author":"Moran","year":"2011","journal-title":"J. Exp. Med."},{"key":"2025030704171638600_r7","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.immuni.2010.04.006","article-title":"Antisocial networking in T helper cells","volume":"32","author":"Pham","year":"2010","journal-title":"Immunity"},{"key":"2025030704171638600_r8","doi-asserted-by":"crossref","first-page":"E2794","DOI":"10.1073\/pnas.1205742109","article-title":"TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation","volume":"109","author":"Nayar","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030704171638600_r9","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.immuni.2013.10.007","article-title":"Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation","volume":"39","author":"Yao","year":"2013","journal-title":"Immunity"},{"key":"2025030704171638600_r10","doi-asserted-by":"crossref","first-page":"5881","DOI":"10.4049\/jimmunol.1303187","article-title":"Graded levels of IRF4 regulate CD8+ T cell differentiation and expansion, but not attrition, in response to acute virus infection","volume":"192","author":"Nayar","year":"2014","journal-title":"J. Immunol."},{"key":"2025030704171638600_r11","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1038\/ni.2710","article-title":"The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells","volume":"14","author":"Man","year":"2013","journal-title":"Nat. Immunol."},{"key":"2025030704171638600_r12","doi-asserted-by":"crossref","first-page":"15019","DOI":"10.1073\/pnas.1309378110","article-title":"The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8+ T cells","volume":"110","author":"Raczkowski","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030704171638600_r13","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.immuni.2013.10.008","article-title":"IRF4 provides rations for cytotoxic CD8(+) T cell soldiers","volume":"39","author":"Huber","year":"2013","journal-title":"Immunity"},{"key":"2025030704171638600_r14","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1084\/jem.20041204","article-title":"Differential requirements for the chemokine receptor CCR7 in T cell activation during Listeria monocytogenes infection","volume":"201","author":"Kursar","year":"2005","journal-title":"J. Exp. Med."},{"key":"2025030704171638600_r15","doi-asserted-by":"crossref","first-page":"9059","DOI":"10.1038\/srep09059","article-title":"The nuclear receptor nr4a1 controls CD8 T cell development through transcriptional suppression of runx3","volume":"5","author":"Nowyhed","year":"2015","journal-title":"Sci. Rep."},{"key":"2025030704171638600_r16","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.cell.2009.03.024","article-title":"A Nurr1 pathway for neuroprotection","volume":"137","author":"Bensinger","year":"2009","journal-title":"Cell"},{"key":"2025030704171638600_r17","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.cell.2009.01.038","article-title":"A Nurr1\/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death","volume":"137","author":"Saijo","year":"2009","journal-title":"Cell"},{"key":"2025030704171638600_r18","doi-asserted-by":"crossref","first-page":"13241","DOI":"10.1073\/pnas.1105118108","article-title":"Positive selecting cell type determines the phenotype of MHC class Ib-restricted CD8+ T cells","volume":"108","author":"Cho","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030704171638600_r19","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nri3307","article-title":"Transcriptional control of effector and memory CD8+ T cell differentiation","volume":"12","author":"Kaech","year":"2012","journal-title":"Nat. Rev. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/8\/3515\/62246700\/1403027.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/8\/3515\/62246700\/1403027.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T04:34:58Z","timestamp":1741322098000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/195\/8\/3515\/7961488"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10]]},"references-count":19,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2015,10,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1403027","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,10]]},"published":{"date-parts":[[2015,10]]}}}