{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:26:30Z","timestamp":1791199590600,"version":"4.2.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2014,6,1]],"date-time":"2014-06-01T00:00:00Z","timestamp":1401580800000},"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":[[2014,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In response to acute virus infections, CD8+ T cells differentiate to form a large population of short-lived effectors and a stable pool of long-lived memory cells. The characteristics of the CD8+ T cell response are influenced by TCR affinity, Ag dose, and the inflammatory cytokine milieu dictated by the infection. To address the mechanism by which differences in TCR signal strength could regulate CD8+ T cell differentiation, we investigated the transcription factor, IFN regulatory factor 4 (IRF4). We show that IRF4 is transiently upregulated to differing levels in murine CD8+ T cells, based on the strength of TCR signaling. In turn, IRF4 controls the magnitude of the CD8+ T cell response to acute virus infection in a dose-dependent manner. Modest differences in IRF4 expression dramatically influence the numbers of short-lived effector cells at the peak of the infection, but have no impact on the kinetics of the infection or on the rate of T cell contraction. Furthermore, the expression of key transcription factors such as T cell factor 1 and Eomesodermin are highly sensitive to graded levels of IRF4. In contrast, T-bet expression is less dependent on IRF4 levels and is influenced by the nature of the infection. These data indicate that IRF4 is a key component that translates the strength of TCR signaling into a graded response of virus-specific CD8+ T cells.<\/jats:p>","DOI":"10.4049\/jimmunol.1303187","type":"journal-article","created":{"date-parts":[[2014,5,17]],"date-time":"2014-05-17T04:19:35Z","timestamp":1400300375000},"page":"5881-5893","source":"Crossref","is-referenced-by-count":114,"title":["Graded Levels of IRF4 Regulate CD8+ T Cell Differentiation and Expansion, but Not Attrition, in Response to Acute Virus Infection"],"prefix":"10.1093","volume":"192","author":[{"given":"Ribhu","family":"Nayar","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Schutten","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Bautista","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Daniels","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L","family":"Prince","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Enos","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A","family":"Brehm","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Medical School , Worcester, MA 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L","family":"Swain","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond M","family":"Welsh","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie J","family":"Berg","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,6,15]]},"reference":[{"key":"2025032404362347800_r1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1146\/annurev.immunol.25.022106.141548","article-title":"Effector and memory CTL differentiation","volume":"25","author":"Williams","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"2025032404362347800_r2","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.immuni.2007.08.007","article-title":"Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection","volume":"27","author":"Kaech","year":"2007","journal-title":"Immunity"},{"key":"2025032404362347800_r3","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/nature07657","article-title":"Complete but curtailed T-cell response to very low-affinity antigen","volume":"458","author":"Zehn","year":"2009","journal-title":"Nature"},{"key":"2025032404362347800_r4","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/ni804","article-title":"Programmed contraction of CD8+ T cells after infection","volume":"3","author":"Badovinac","year":"2002","journal-title":"Nat. Immunol."},{"key":"2025032404362347800_r5","doi-asserted-by":"crossref","first-page":"6833","DOI":"10.4049\/jimmunol.165.12.6833","article-title":"Early programming of T cell populations responding to bacterial infection","volume":"165","author":"Mercado","year":"2000","journal-title":"J. Immunol."},{"key":"2025032404362347800_r6","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1084\/jem.20060928","article-title":"Duration of the initial TCR stimulus controls the magnitude but not functionality of the CD8+ T cell response","volume":"203","author":"Prlic","year":"2006","journal-title":"J. Exp. Med."},{"key":"2025032404362347800_r7","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.immuni.2009.05.014","article-title":"Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties","volume":"31","author":"Rutishauser","year":"2009","journal-title":"Immunity"},{"key":"2025032404362347800_r8","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.immuni.2007.07.010","article-title":"Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor","volume":"27","author":"Joshi","year":"2007","journal-title":"Immunity"},{"key":"2025032404362347800_r9","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.immuni.2009.06.021","article-title":"Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses","volume":"31","author":"Kallies","year":"2009","journal-title":"Immunity"},{"key":"2025032404362347800_r10","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.immuni.2010.08.002","article-title":"Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1","volume":"33","author":"Zhou","year":"2010","journal-title":"Immunity"},{"key":"2025032404362347800_r11","doi-asserted-by":"crossref","first-page":"4988","DOI":"10.4049\/jimmunol.1002042","article-title":"Cutting edge: the transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche","volume":"185","author":"Banerjee","year":"2010","journal-title":"J. Immunol."},{"key":"2025032404362347800_r12","doi-asserted-by":"crossref","first-page":"9777","DOI":"10.1073\/pnas.0914127107","article-title":"Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory","volume":"107","author":"Jeannet","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032404362347800_r13","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.immuni.2011.09.017","article-title":"An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells","volume":"35","author":"Cui","year":"2011","journal-title":"Immunity"},{"key":"2025032404362347800_r14","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1093\/nar\/23.12.2127","article-title":"Molecular cloning of LSIRF, a lymphoid-specific member of the interferon regulatory factor family that binds the interferon-stimulated response element (ISRE)","volume":"23","author":"Matsuyama","year":"1995","journal-title":"Nucleic Acids Res."},{"key":"2025032404362347800_r15","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1101\/gad.9.11.1377","article-title":"Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator","volume":"9","author":"Eisenbeis","year":"1995","journal-title":"Genes Dev."},{"key":"2025032404362347800_r16","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.immuni.2006.07.009","article-title":"Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation","volume":"25","author":"Sciammas","year":"2006","journal-title":"Immunity"},{"key":"2025032404362347800_r17","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1126\/science.275.5299.540","article-title":"Requirement for the transcription factor LSIRF\/IRF4 for mature B and T lymphocyte function","volume":"275","author":"Mittr\u00fccker","year":"1997","journal-title":"Science"},{"key":"2025032404362347800_r18","doi-asserted-by":"crossref","first-page":"11808","DOI":"10.1073\/pnas.182425099","article-title":"Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4","volume":"99","author":"Lohoff","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032404362347800_r19","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1084\/jem.20011128","article-title":"Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression","volume":"195","author":"Rengarajan","year":"2002","journal-title":"J. Exp. Med."},{"key":"2025032404362347800_r20","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.immuni.2010.07.014","article-title":"Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells","volume":"33","author":"Staudt","year":"2010","journal-title":"Immunity"},{"key":"2025032404362347800_r21","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/ni1500","article-title":"The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4","volume":"8","author":"Br\u00fcstle","year":"2007","journal-title":"Nat. Immunol."},{"key":"2025032404362347800_r22","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1172\/JCI63681","article-title":"IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis","volume":"123","author":"Huber","year":"2013","journal-title":"J. Clin. Invest."},{"key":"2025032404362347800_r23","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.immuni.2009.02.007","article-title":"Critical regulation of early Th17 cell differentiation by interleukin-1 signaling","volume":"30","author":"Chung","year":"2009","journal-title":"Immunity"},{"key":"2025032404362347800_r24","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":"2025032404362347800_r25","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/ni.2006","article-title":"The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells","volume":"12","author":"Cretney","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025032404362347800_r26","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":"2025032404362347800_r27","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/ni1357","article-title":"Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination","volume":"7","author":"Klein","year":"2006","journal-title":"Nat. Immunol."},{"key":"2025032404362347800_r28"},{"key":"2025032404362347800_r29","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/342559a0","article-title":"Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen","volume":"342","author":"Pircher","year":"1989","journal-title":"Nature"},{"key":"2025032404362347800_r30","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1038\/nm1114","article-title":"TCR affinity and negative regulation limit autoimmunity","volume":"10","author":"Gronski","year":"2004","journal-title":"Nat. Med."},{"key":"2025032404362347800_r31","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/ni1268","article-title":"Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin","volume":"6","author":"Intlekofer","year":"2005","journal-title":"Nat. Immunol."},{"key":"2025032404362347800_r32","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":"2025032404362347800_r33","doi-asserted-by":"crossref","first-page":"6670","DOI":"10.4049\/jimmunol.1000159","article-title":"The Pim kinase pathway contributes to survival signaling in primed CD8+ T cells upon CD27 costimulation","volume":"185","author":"Peperzak","year":"2010","journal-title":"J. Immunol."},{"key":"2025032404362347800_r34","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.4049\/jimmunol.156.3.1138","article-title":"An absolute and restricted requirement for IL-12 in natural killer cell IFN-\u03b3 production and antiviral defense: studies of natural killer and T cell responses in contrasting viral infections","volume":"156","author":"Orange","year":"1996","journal-title":"J. Immunol."},{"key":"2025032404362347800_r35","doi-asserted-by":"crossref","first-page":"4825","DOI":"10.1128\/JVI.72.6.4825-4831.1998","article-title":"Role of interleukin-12 in primary influenza virus infection","volume":"72","author":"Monteiro","year":"1998","journal-title":"J. Virol."},{"key":"2025032404362347800_r36","doi-asserted-by":"crossref","first-page":"7515","DOI":"10.4049\/jimmunol.177.11.7515","article-title":"Cutting edge: IL-12 inversely regulates T-bet and eomesodermin expression during pathogen-induced CD8+ T cell differentiation","volume":"177","author":"Takemoto","year":"2006","journal-title":"J. Immunol."},{"key":"2025032404362347800_r37","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1006\/viro.1997.8934","article-title":"Identification of Db- and Kb-restricted subdominant cytotoxic T-cell responses in lymphocytic choriomeningitis virus-infected mice","volume":"240","author":"van der Most","year":"1998","journal-title":"Virology"},{"key":"2025032404362347800_r38","doi-asserted-by":"crossref","first-page":"6704","DOI":"10.4049\/jimmunol.179.10.6704","article-title":"Strength of stimulus and clonal competition impact the rate of memory CD8 T cell differentiation","volume":"179","author":"Sarkar","year":"2007","journal-title":"J. Immunol."},{"key":"2025032404362347800_r39","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/87720","article-title":"Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in na\u00efve cells","volume":"2","author":"Kaech","year":"2001","journal-title":"Nat. Immunol."},{"key":"2025032404362347800_r40","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/87730","article-title":"Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation","volume":"2","author":"van Stipdonk","year":"2001","journal-title":"Nat. Immunol."},{"key":"2025032404362347800_r41","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":"2025032404362347800_r42","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.immuni.2012.09.017","article-title":"Pathogen-specific inflammatory milieux tune the antigen sensitivity of CD8+ T cells by enhancing T cell receptor signaling","volume":"38","author":"Richer","year":"2013","journal-title":"Immunity"},{"key":"2025032404362347800_r43","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1146\/annurev.immunol.22.012703.104743","article-title":"Tec family kinases in T lymphocyte development and function","volume":"23","author":"Berg","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"2025032404362347800_r44","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"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/192\/12\/5881\/61762324\/1303187.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/192\/12\/5881\/61762324\/1303187.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T11:53:36Z","timestamp":1742817216000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/192\/12\/5881\/8001779"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6]]},"references-count":44,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2014,6,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1303187","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.718391914.793505123","asserted-by":"object"}]},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,6]]},"published":{"date-parts":[[2014,6]]}}}