{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:22:58Z","timestamp":1790832178509,"version":"4.1.0"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T00:00:00Z","timestamp":1713139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI148403"],"award-info":[{"award-number":["AI148403"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In response to acute infection, naive CD4+ T cells primarily differentiate into T helper 1 (Th1) or T follicular helper (Tfh) cells that play critical roles in orchestrating cellular or humoral arms of immunity, respectively. However, despite the well established role of T-bet and BCL-6 in driving Th1 and Tfh cell lineage commitment, respectively, whether additional transcriptional circuits also underlie the fate bifurcation of Th1 and Tfh cell subsets is not fully understood. In this article, we study how the transcriptional regulator Bhlhe40 dictates the Th1\/Tfh differentiation axis in mice. CD4+ T cell\u2013specific deletion of Bhlhe40 abrogates Th1 but augments Tfh differentiation. We also assessed an increase in germinal center B cells and Ab production, suggesting that deletion of Bhlhe40 in CD4+ T cells not only alters Tfh differentiation but also their capacity to provide help to B cells. To identify molecular mechanisms by which Bhlhe40 regulates Th1 versus Tfh lineage choice, we first performed epigenetic profiling in the virus specific Th1 and Tfh cells following LCMV infection, which revealed distinct promoter and enhancer activities between the two helper cell lineages. Furthermore, we identified that Bhlhe40 directly binds to cis-regulatory elements of Th1-related genes such as Tbx21 and Cxcr6 to activate their expression while simultaneously binding to regions of Tfh-related genes such as Bcl6 and Cxcr5 to repress their expression. Collectively, our data suggest that Bhlhe40 functions as a transcription activator to promote Th1 cell differentiation and a transcription repressor to suppress Tfh cell differentiation.<\/jats:p>","DOI":"10.4049\/jimmunol.2300355","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T09:03:15Z","timestamp":1713171795000},"page":"1829-1842","source":"Crossref","is-referenced-by-count":15,"title":["Bhlhe40 Promotes CD4+ T Helper 1 Cell and Suppresses T Follicular Helper Cell Differentiation during Viral Infection"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5750-8134","authenticated-orcid":false,"given":"Christine","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI"},{"name":"Versiti Blood Research Institute, Versiti Wisconsin , Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4140-6707","authenticated-orcid":false,"given":"Matthew","family":"Kudek","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI"},{"name":"Versiti Blood Research Institute, Versiti Wisconsin , Milwaukee, WI"},{"name":"Department of Pediatrics, Medical College of Wisconsin , Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7431-8535","authenticated-orcid":false,"given":"Ryan","family":"Zander","sequence":"additional","affiliation":[{"name":"Versiti Blood Research Institute, Versiti Wisconsin , Milwaukee, WI"},{"name":"Department of Microbiology and Immunology, University of Iowa , Iowa City, IA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0657-6096","authenticated-orcid":false,"given":"Hongshen","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Northwestern University , Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8398-2318","authenticated-orcid":false,"given":"Jian","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI"},{"name":"Versiti Blood Research Institute, Versiti Wisconsin , Milwaukee, WI"},{"name":"Department of Pathology, Northwestern University , Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8124-6135","authenticated-orcid":false,"given":"Ashley","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI"},{"name":"Versiti Blood Research Institute, Versiti Wisconsin , Milwaukee, WI"},{"name":"Department of Pathology, Northwestern University , Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8400-7534","authenticated-orcid":false,"given":"Donia","family":"Alson","sequence":"additional","affiliation":[{"name":"Versiti Blood Research Institute, Versiti Wisconsin , Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achia","family":"Khatun","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI"},{"name":"Versiti Blood Research Institute, Versiti Wisconsin , Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI"},{"name":"Versiti Blood Research Institute, Versiti Wisconsin , Milwaukee, WI"},{"name":"Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2347-4511","authenticated-orcid":false,"given":"Jie","family":"Sun","sequence":"additional","affiliation":[{"name":"University of Virginia School of Medicine , Charlottesville, VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7121-6499","authenticated-orcid":false,"given":"William","family":"Drobyski","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI"},{"name":"Department of Medicine, Medical College of Wisconsin , Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2856-7650","authenticated-orcid":false,"given":"Brian T","family":"Edelson","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguo","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI"},{"name":"Versiti Blood Research Institute, Versiti Wisconsin , Milwaukee, WI"},{"name":"Department of Pathology, Northwestern University , Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,4,15]]},"reference":[{"key":"2025020405502116500_r1","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1084\/jem.20101773","article-title":"Viral persistence redirects CD4 T cell 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