{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:09:17Z","timestamp":1788786557138,"version":"build-2803163510"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health","award":["R01 AI137238"],"award-info":[{"award-number":["R01 AI137238"]}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health","award":["R01AI182215"],"award-info":[{"award-number":["R01AI182215"]}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health","award":["R01AI194555"],"award-info":[{"award-number":["R01AI194555"]}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute of the NIH","doi-asserted-by":"crossref","award":["5P30CA042014-24"],"award-info":[{"award-number":["5P30CA042014-24"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute of the NIH","doi-asserted-by":"crossref","award":["1S10RR026802-01"],"award-info":[{"award-number":["1S10RR026802-01"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute of the NIH","doi-asserted-by":"crossref","award":["P30CA042014"],"award-info":[{"award-number":["P30CA042014"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Following acute viral infection, na\u00efve CD4+ T cells differentiate into T helper 1 (Th1) and T follicular helper (Tfh) cells. The transcription factor Ets1 represses Tfh cell formation and function following protein immunization; however, whether Ets1 regulates Tfh differentiation in viral infection is unclear. Here, we demonstrate that during acute viral infection, conditional deletion of Ets1 in CD4+ T cells impairs germinal center (GC) Tfh differentiation and function, resulting in diminished GC B-cell responses, reduced IgG2c class switching, and impaired antibody production. Mechanistically, Ets1 deficiency results in aberrant upregulation of Blimp1 to negatively impact early Tfh and GC Tfh cell differentiation in a cell-intrinsic manner. Early Tfh differentiation is partially restored by knockdown of Blimp1 in Ets1-deficient T cells. In contrast, during protein immunization where Blimp1 is not highly expressed, Ets1 is not required to repress expression of CD25 and Blimp1 in early Tfh cells, and Ets1 deficiency results in a cell-intrinsic enhancement in GC Tfh differentiation. Collectively, these results demonstrate that Ets1 is a positive regulator of GC Tfh cell differentiation and function during viral infection, highlighting a context-dependent role for Ets1 in GC Tfh cell responses.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag096","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T07:40:01Z","timestamp":1778830801000},"source":"Crossref","is-referenced-by-count":0,"title":["Ets1 represses Blimp1 to promote germinal center T follicular helper cell differentiation during viral infection"],"prefix":"10.1093","volume":"215","author":[{"given":"Bryant","family":"Perkins","sequence":"first","affiliation":[{"name":"Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine , Salt Lake City, UT,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryce","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine , Salt Lake City, UT,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen X","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine , Salt Lake City, UT,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4721-4482","authenticated-orcid":false,"given":"Matthew A","family":"Williams","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine , Salt Lake City, UT,","place":["United States"]},{"name":"Huntsman Cancer Institute, University of Utah Health , Salt Lake City, UT,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Scott","family":"Hale","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine , Salt Lake City, UT,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"2026090708270805000_vkag096-B1","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1016\/j.immuni.2019.04.011","article-title":"T follicular helper cell biology: a decade of discovery and diseases","volume":"50","author":"Crotty","year":"2019","journal-title":"Immunity"},{"key":"2026090708270805000_vkag096-B2","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1126\/science.1175870","article-title":"Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation","volume":"325","author":"Johnston","year":"2009","journal-title":"Science"},{"key":"2026090708270805000_vkag096-B3","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1126\/science.1176676","article-title":"Bcl6 mediates the development of T follicular helper cells","volume":"325","author":"Nurieva","year":"2009","journal-title":"Science"},{"key":"2026090708270805000_vkag096-B4","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.immuni.2009.07.002","article-title":"The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment","volume":"31","author":"Yu","year":"2009","journal-title":"Immunity"},{"key":"2026090708270805000_vkag096-B5","doi-asserted-by":"publisher","first-page":"176ra32","DOI":"10.1126\/scitranslmed.3005191","article-title":"Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination","volume":"5","author":"Bentebibel","year":"2013","journal-title":"Sci Transl Med"},{"key":"2026090708270805000_vkag096-B6","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1016\/j.cell.2019.04.012","article-title":"Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance","volume":"177","author":"Cirelli","year":"2019","journal-title":"Cell"},{"key":"2026090708270805000_vkag096-B7","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/j.immuni.2013.08.031","article-title":"Human circulating PD-1+CXCR3\u2212CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses","volume":"39","author":"Locci","year":"2013","journal-title":"Immunity"},{"key":"2026090708270805000_vkag096-B8","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1016\/j.celrep.2016.10.085","article-title":"Direct probing of germinal center responses reveals immunological features and bottlenecks for neutralizing antibody responses to HIV env trimer","volume":"17","author":"Havenar-Daughton","year":"2016","journal-title":"Cell Rep"},{"key":"2026090708270805000_vkag096-B9","doi-asserted-by":"publisher","first-page":"eaan8405","DOI":"10.1126\/scitranslmed.aan8405","article-title":"Circulating T(FH) cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity","volume":"10","author":"Koutsakos","year":"2018","journal-title":"Sci Transl Med"},{"key":"2026090708270805000_vkag096-B10","doi-asserted-by":"publisher","first-page":"e20201254","DOI":"10.1084\/jem.20201254","article-title":"Modulating the quantity of HIV Env-specific CD4 T cell help promotes rare B cell responses in germinal centers","volume":"218","author":"Lee","year":"2021","journal-title":"J Exp Med"},{"key":"2026090708270805000_vkag096-B11","doi-asserted-by":"publisher","first-page":"aag0851","DOI":"10.1126\/sciimmunol.aag0851","article-title":"Immune perturbations in HIV-1\u2013infected individuals who make broadly neutralizing antibodies","volume":"1","author":"Moody","year":"2016","journal-title":"Sci Immunol"},{"key":"2026090708270805000_vkag096-B12","doi-asserted-by":"publisher","first-page":"3094","DOI":"10.1016\/j.immuni.2025.10.008","article-title":"Highly functional and prolonged germinal center T follicular helper cell responses are associated with enhanced neutralizing antibody development","volume":"58","author":"Marina-Z\u00e1rate","year":"2025","journal-title":"Immunity"},{"key":"2026090708270805000_vkag096-B13","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1084\/jem.20141380","article-title":"BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms","volume":"212","author":"Hatzi","year":"2015","journal-title":"J Exp Med"},{"key":"2026090708270805000_vkag096-B14","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.immuni.2015.01.017","article-title":"ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation","volume":"42","author":"Stone","year":"2015","journal-title":"Immunity"},{"key":"2026090708270805000_vkag096-B15","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1084\/jem.20141432","article-title":"ICOS maintains the T follicular helper cell phenotype by down-regulating Kr\u00fcppel-like factor 2","volume":"212","author":"Weber","year":"2015","journal-title":"J Exp Med"},{"key":"2026090708270805000_vkag096-B16","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1016\/j.immuni.2011.03.023","article-title":"ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6","volume":"34","author":"Choi","year":"2011","journal-title":"Immunity"},{"key":"2026090708270805000_vkag096-B17","doi-asserted-by":"publisher","first-page":"5099","DOI":"10.4049\/jimmunol.179.8.5099","article-title":"Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation","volume":"179","author":"Haynes","year":"2007","journal-title":"J Immunol"},{"key":"2026090708270805000_vkag096-B18","doi-asserted-by":"publisher","first-page":"801","DOI":"10.4049\/jimmunol.1900581","article-title":"Cutting edge: Tcf1 instructs T follicular helper cell differentiation by repressing Blimp1 in response to acute viral infection","volume":"203","author":"Shao","year":"2019","journal-title":"J Immunol"},{"key":"2026090708270805000_vkag096-B19","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1038\/ni.3226","article-title":"LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6","volume":"16","author":"Choi","year":"2015","journal-title":"Nat Immunol"},{"key":"2026090708270805000_vkag096-B20","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1038\/ni.3461","article-title":"Id2 reinforces TH1 differentiation and inhibits E2A to repress TFH differentiation","volume":"17","author":"Shaw","year":"2016","journal-title":"Nat Immunol"},{"key":"2026090708270805000_vkag096-B21","doi-asserted-by":"publisher","first-page":"2099","DOI":"10.1016\/j.celrep.2015.08.049","article-title":"TCF1 is required for the T follicular helper cell response to viral infection","volume":"12","author":"Wu","year":"2015","journal-title":"Cell Rep"},{"key":"2026090708270805000_vkag096-B22","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1084\/jem.20111174","article-title":"STAT5 is a potent negative regulator of TFH cell differentiation","volume":"209","author":"Johnston","year":"2012","journal-title":"J Exp Med"},{"key":"2026090708270805000_vkag096-B23","doi-asserted-by":"publisher","first-page":"586","DOI":"10.4049\/jimmunol.2300570","article-title":"Effector-phase IL-2 signals drive Th1 effector and memory responses dependently and independently of TCF-1","volume":"212","author":"Charley","year":"2024","journal-title":"J Immunol"},{"key":"2026090708270805000_vkag096-B24","doi-asserted-by":"publisher","first-page":"4014","DOI":"10.4049\/jimmunol.1202963","article-title":"Bcl6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory","volume":"190","author":"Choi","year":"2013","journal-title":"J Immunol"},{"key":"2026090708270805000_vkag096-B25","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1038\/s41590-020-0706-5","article-title":"Bcl-6 is the nexus transcription factor of T follicular helper cells via repressor-of-repressor circuits","volume":"21","author":"Choi","year":"2020","journal-title":"Nat Immunol"},{"key":"2026090708270805000_vkag096-B26","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1038\/s41590-021-01086-x","article-title":"Hierarchical regulation of the resting and activated T cell epigenome by major transcription factor families","volume":"23","author":"Zhong","year":"2022","journal-title":"Nat Immunol"},{"key":"2026090708270805000_vkag096-B27","doi-asserted-by":"publisher","first-page":"eabm4982","DOI":"10.1126\/sciadv.abm4982","article-title":"Tet2 coordinates with Foxo1 and Runx1 to balance T follicular helper cell and T helper 1 cell differentiation","volume":"8","author":"Baessler","year":"2022","journal-title":"Sci Adv"},{"key":"2026090708270805000_vkag096-B28","doi-asserted-by":"publisher","first-page":"e2218324120","DOI":"10.1073\/pnas.2218324120","article-title":"Tet2 deletion in CD4+ T cells disrupts Th1 lineage commitment in memory cells and enhances T follicular helper cell recall responses to viral rechallenge","volume":"120","author":"Baessler","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026090708270805000_vkag096-B29","doi-asserted-by":"publisher","first-page":"117062","DOI":"10.1016\/j.celrep.2026.117062","article-title":"Dnmt3a-dependent de novo DNA methylation enforces lineage commitment and preserves functionality of memory Th1 and Tfh cells","volume":"45","author":"Perkins","year":"2026","journal-title":"Cell Rep"},{"key":"2026090708270805000_vkag096-B30","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1016\/j.immuni.2018.10.012","article-title":"The transcription factor Ets1 suppresses T follicular helper type 2 cell differentiation to halt the onset of systemic lupus erythematosus","volume":"49","author":"Kim","year":"2018","journal-title":"Immunity"},{"key":"2026090708270805000_vkag096-B31","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.4049\/jimmunol.2100210","article-title":"Protein immunization induces memory CD4(+) T cells that lack Th lineage commitment","volume":"207","author":"Sircy","year":"2021","journal-title":"J Immunol"},{"key":"2026090708270805000_vkag096-B32","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1084\/jem.20041330","article-title":"Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses","volume":"201","author":"Grenningloh","year":"2005","journal-title":"J Exp Med"},{"key":"2026090708270805000_vkag096-B33","doi-asserted-by":"publisher","first-page":"15776","DOI":"10.1073\/pnas.1304343110","article-title":"Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter","volume":"110","author":"Tsao","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026090708270805000_vkag096-B34","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1016\/j.immuni.2023.05.004","article-title":"Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation","volume":"56","author":"Chandra","year":"2023","journal-title":"Immunity"},{"key":"2026090708270805000_vkag096-B35","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1084\/jem.20150851","article-title":"The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2","volume":"213","author":"Zook","year":"2016","journal-title":"J Exp Med"},{"key":"2026090708270805000_vkag096-B36","doi-asserted-by":"publisher","first-page":"W45","DOI":"10.1093\/nar\/gkae358","article-title":"ChIP-Atlas 3.0: a data-mining suite to explore chromosome architecture together with large-scale regulome data","volume":"52","author":"Zou","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"2026090708270805000_vkag096-B37","doi-asserted-by":"publisher","first-page":"W175","DOI":"10.1093\/nar\/gkac199","article-title":"ChIP-Atlas 2021 update: a data-mining suite for exploring epigenomic landscapes by fully integrating ChIP-seq, ATAC-seq and Bisulfite-seq data","volume":"50","author":"Zou","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"2026090708270805000_vkag096-B38","doi-asserted-by":"publisher","first-page":"e46255","DOI":"10.15252\/embr.201846255","article-title":"ChIP-Atlas: a data-mining suite powered by full integration of public ChIP-seq data","volume":"19","author":"Oki","year":"2018","journal-title":"EMBO Rep"},{"key":"2026090708270805000_vkag096-B39","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1016\/j.celrep.2019.09.064","article-title":"Batf pioneers the reorganization of chromatin in developing effector T cells via Ets1-dependent recruitment of Ctcf","volume":"29","author":"Pham","year":"2019","journal-title":"Cell Rep"},{"key":"2026090708270805000_vkag096-B40","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1007\/978-1-61779-430-8_19","article-title":"Utilizing a retroviral RNAi system to investigate in vivo mTOR functions in T cells","volume":"821","author":"Araki","year":"2012","journal-title":"Methods Mol Biol"},{"key":"2026090708270805000_vkag096-B41","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1146\/annurev.biochem.79.081507.103945","article-title":"Genomic and biochemical insights into the specificity of ETS transcription factors","volume":"80","author":"Hollenhorst","year":"2011","journal-title":"Annu Rev Biochem"},{"key":"2026090708270805000_vkag096-B42","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1002\/(sici)1521-4141(199801)28:01&lt;390::Aid-immu390&gt;3.0.CO;2-o","article-title":"Virus-specific MHC-class II-restricted TCR-transgenic mice: effects on humoral and cellular immune responses after viral infection","volume":"28","author":"Oxenius","year":"1998","journal-title":"Eur J Immunol"},{"key":"2026090708270805000_vkag096-B43","doi-asserted-by":"publisher","first-page":"1895","DOI":"10.1128\/jvi.69.3.1895-1902.1995","article-title":"Bone marrow is a major site of long-term antibody production after acute viral infection","volume":"69","author":"Slifka","year":"1995","journal-title":"J Virol"},{"key":"2026090708270805000_vkag096-B44","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.1126\/science.8009221","article-title":"Functional role of type I and type II interferons in antiviral defense","volume":"264","author":"M\u00fcller","year":"1994","journal-title":"Science"},{"key":"2026090708270805000_vkag096-B45","doi-asserted-by":"publisher","first-page":"383","DOI":"10.3389\/fimmu.2017.00383","article-title":"Genome-wide identification of target genes for the key B cell transcription factor Ets1","volume":"8","author":"Saelee","year":"2017","journal-title":"Front Immunol"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/215\/5\/vkag096\/68290377\/vkag096.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/215\/5\/vkag096\/68290377\/vkag096.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:27:16Z","timestamp":1788784036000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/doi\/10.1093\/jimmun\/vkag096\/8678681"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":45,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5,14]]}},"URL":"https:\/\/doi.org\/10.1093\/jimmun\/vkag096","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,5]]},"published":{"date-parts":[[2026,5]]},"article-number":"vkag096"}}