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Following mouse CMV infection, Bhlhe40 was the most highly induced transcription factor in NK cells among the basic helix-loop-helix family. Bhlhe40 upregulation in NK cells depended upon IL-12 and IL-18 signals, with the promoter of Bhlhe40 enriched for STAT4 and the permissive histone H3K4me3, and with STAT4-deficient NK cells showing an impairment of Bhlhe40 induction and diminished H3K4me3. Transcriptomic and protein analysis of Bhlhe40-deficient NK cells revealed a defect in IFN-\u03b3 production during mouse CMV infection, resulting in diminished protective immunity following viral challenge. Finally, we provide evidence that Bhlhe40 directly promotes IFN-\u03b3 by binding throughout the Ifng loci in activated NK cells. Thus, our study reveals how STAT4-mediated control of Bhlhe40 drives protective IFN-\u03b3 secretion by NK cells during viral infection.<\/jats:p>","DOI":"10.4049\/jimmunol.2300402","type":"journal-article","created":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T08:23:35Z","timestamp":1697185415000},"page":"1469-1474","source":"Crossref","is-referenced-by-count":9,"title":["Cutting Edge: STAT4 Promotes\n                    <i>Bhlhe40<\/i>\n                    Induction to Drive Protective IFN-\u03b3 from NK Cells during Viral Infection"],"prefix":"10.1093","volume":"211","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6452-8152","authenticated-orcid":false,"given":"Hyunu","family":"Kim","sequence":"first","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center , New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9323-0176","authenticated-orcid":false,"given":"Aamna","family":"Abbasi","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center , New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Sharrock","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center , New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Endi K","family":"Santosa","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center , New York, NY"},{"name":"Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College , New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Sheppard","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center , New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen M","family":"Lau","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center , New York, NY"}],"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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8062-9033","authenticated-orcid":false,"given":"Joseph C","family":"Sun","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center , New York, NY"},{"name":"Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College , New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,13]]},"reference":[{"key":"2026041420284671600_r1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1146\/annurev-immunol-101819-074948","article-title":"Natural killer cells: from innate to adaptive features","volume":"39","author":"Mujal","year":"2021","journal-title":"Annu. 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