{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:45:27Z","timestamp":1787910327869,"version":"build-2784847793"},"reference-count":89,"publisher":"Rockefeller University Press","issue":"2","license":[{"start":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T00:00:00Z","timestamp":1639699200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T00:00:00Z","timestamp":1659916800000},"content-version":"vor","delay-in-days":234,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","award":["2017-01118"],"award-info":[{"award-number":["2017-01118"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","award":["2018-05973"],"award-info":[{"award-number":["2018-05973"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["CAN 2018\/710"],"award-info":[{"award-number":["CAN 2018\/710"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007435","name":"\u00c5ke Wiberg Stiftelse","doi-asserted-by":"publisher","award":["M18-0094"],"award-info":[{"award-number":["M18-0094"]}],"id":[{"id":"10.13039\/100007435","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P28841"],"award-info":[{"award-number":["P28841"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001388","name":"Wenner-Gren Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001388","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["DU 1964\/1-1"],"award-info":[{"award-number":["DU 1964\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["RE 4264\/1-1"],"award-info":[{"award-number":["RE 4264\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008349","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020","doi-asserted-by":"publisher","award":["740349-PlasmaCellControl"],"award-info":[{"award-number":["740349-PlasmaCellControl"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["075-15-2020-784"],"award-info":[{"award-number":["075-15-2020-784"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,2,7]]},"abstract":"<jats:p>The generation of high-affinity antibodies against pathogens and vaccines requires the germinal center (GC) reaction, which relies on a complex interplay between specialized effector B and CD4 T lymphocytes, the GC B cells and T follicular helper (TFH) cells. Intriguingly, several positive key regulators of the GC reaction are common for both cell types. Here, we report that the transcription factor Bhlhe40 is a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction. In activated CD4 T cells, Bhlhe40 was required to restrain proliferation, thus limiting the number of TFH cells. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GC B cells but not of early memory B cells or plasmablasts. Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by the accumulation of monoclonal GC B-like cells and polyclonal TFH cells in various tissues.<\/jats:p>","DOI":"10.1084\/jem.20211406","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T02:21:51Z","timestamp":1637720511000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":35,"title":["Bhlhe40 function in activated B and TFH cells restrains the GC reaction and prevents lymphomagenesis"],"prefix":"10.1084","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1073-4046","authenticated-orcid":true,"given":"Ren\u00e9","family":"Rauschmeier","sequence":"first","affiliation":[{"name":"Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7468-9985","authenticated-orcid":true,"given":"Annika","family":"Reinhardt","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Immunology and Allergy, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden 2"},{"name":"Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4997-6795","authenticated-orcid":true,"given":"Charlotte","family":"Gustafsson","sequence":"additional","affiliation":[{"name":"Center for Hematology and Regenerative Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6211-9515","authenticated-orcid":true,"given":"Vassilis","family":"Glaros","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Immunology and Allergy, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden 2"},{"name":"Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0056-4549","authenticated-orcid":true,"given":"Artem V.","family":"Artemov","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology, Medical University of Vienna, Vienna, Austria 5"},{"name":"Endocrinology Research Centre, Moscow, Russian Federation 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0061-0901","authenticated-orcid":true,"given":"Josefine","family":"Dunst","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Immunology and Allergy, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden 2"},{"name":"Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6214-6177","authenticated-orcid":true,"given":"Reshma","family":"Taneja","sequence":"additional","affiliation":[{"name":"Department of Physiology, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5471-0356","authenticated-orcid":true,"given":"Igor","family":"Adameyko","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology, Medical University of Vienna, Vienna, Austria 5"},{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0738-0328","authenticated-orcid":true,"given":"Robert","family":"M\u00e5nsson","sequence":"additional","affiliation":[{"name":"Center for Hematology and Regenerative Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden 4"},{"name":"Hematology Center, Karolinska University Hospital, Stockholm, Sweden 9"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9111-9351","authenticated-orcid":true,"given":"Meinrad","family":"Busslinger","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6672-1914","authenticated-orcid":true,"given":"Taras","family":"Kreslavsky","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Immunology and Allergy, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden 2"},{"name":"Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2021,12,17]]},"reference":[{"key":"2023072819545488600_bib1","doi-asserted-by":"publisher","first-page":"W537","DOI":"10.1093\/nar\/gky379","article-title":"The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update","volume":"46","author":"Afgan","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2023072819545488600_bib2","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq--a Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics."},{"key":"2023072819545488600_bib3","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1038\/nri3814","article-title":"Germinal centres and B cell lymphomagenesis","volume":"15","author":"Basso","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"2023072819545488600_bib4","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.immuni.2012.11.020","article-title":"Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype","volume":"38","author":"Baumjohann","year":"2013","journal-title":"Immunity."},{"key":"2023072819545488600_bib5","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1084\/jem.20110578","article-title":"Loss of Roquin induces early death and immune deregulation but not autoimmunity","volume":"208","author":"Bertossi","year":"2011","journal-title":"J. Exp. Med."},{"key":"2023072819545488600_bib6","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1084\/jem.20091548","article-title":"Batf coordinates multiple aspects of B and T cell function required for normal antibody responses","volume":"207","author":"Betz","year":"2010","journal-title":"J. Exp. Med."},{"key":"2023072819545488600_bib7","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/imr.12890","article-title":"T cell help to B cells: Cognate and atypical interactions in peripheral and intestinal lymphoid tissues","volume":"296","author":"Biram","year":"2020","journal-title":"Immunol. Rev."},{"key":"2023072819545488600_bib8","doi-asserted-by":"publisher","DOI":"10.1088\/1742-5468\/2008\/10\/P10008","article-title":"Fast unfolding of communities in large networks","volume":"2008","author":"Blondel","year":"2008","journal-title":"J. Stat. Mech."},{"key":"2023072819545488600_bib9","doi-asserted-by":"publisher","first-page":"8664","DOI":"10.1073\/pnas.1205834109","article-title":"Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation","volume":"109","author":"Bollig","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072819545488600_bib10","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1038\/nmeth.2688","article-title":"Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position","volume":"10","author":"Buenrostro","year":"2013","journal-title":"Nat. Methods."},{"key":"2023072819545488600_bib11","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1038\/ni.2418","article-title":"The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers","volume":"13","author":"Calado","year":"2012","journal-title":"Nat. Immunol."},{"key":"2023072819545488600_bib12","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/j.ccr.2005.03.037","article-title":"Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice","volume":"7","author":"Cattoretti","year":"2005","journal-title":"Cancer Cell."},{"key":"2023072819545488600_bib13","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1186\/s12967-018-1578-4","article-title":"PBMC fixation and processing for Chromium single-cell RNA sequencing","volume":"16","author":"Chen","year":"2018","journal-title":"J. Transl. Med."},{"key":"2023072819545488600_bib14","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1136\/jclinpath-2016-204065","article-title":"T cell-rich lymphoid infiltrates with large B cells: a review of key entities and diagnostic approach","volume":"70","author":"Cheng","year":"2017","journal-title":"J. Clin. Pathol."},{"key":"2023072819545488600_bib15","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1016\/j.immuni.2016.07.023","article-title":"The Transcription Factor AP4 Mediates Resolution of Chronic Viral Infection through Amplification of Germinal Center B Cell Responses","volume":"45","author":"Chou","year":"2016","journal-title":"Immunity."},{"key":"2023072819545488600_bib16","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."},{"issue":"Database issue","key":"2023072819545488600_bib17","doi-asserted-by":"publisher","first-page":"D662","DOI":"10.1093\/nar\/gku1010","article-title":"Ensembl 2015","volume":"43","author":"Cunningham","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2023072819545488600_bib18","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1002\/immu.200310005","article-title":"Transgenic mice with hematopoietic and lymphoid specific expression of Cre","volume":"33","author":"de Boer","year":"2003","journal-title":"Eur. J. Immunol."},{"key":"2023072819545488600_bib19","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/nri3804","article-title":"Dynamics of B cells in germinal centres","volume":"15","author":"De Silva","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"2023072819545488600_bib20","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1084\/jem.191.3.485","article-title":"Germinal centers without T cells","volume":"191","author":"de Vinuesa","year":"2000","journal-title":"J. Exp. Med."},{"key":"2023072819545488600_bib21","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1126\/science.276.5312.589","article-title":"Control of inflammation, cytokine expression, and germinal center formation by BCL-6","volume":"276","author":"Dent","year":"1997","journal-title":"Science."},{"key":"2023072819545488600_bib22","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics."},{"key":"2023072819545488600_bib23","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1038\/ni.2428","article-title":"The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry","volume":"13","author":"Dominguez-Sola","year":"2012","journal-title":"Nat. Immunol."},{"key":"2023072819545488600_bib24","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1016\/j.immuni.2015.10.015","article-title":"The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program","volume":"43","author":"Dominguez-Sola","year":"2015","journal-title":"Immunity."},{"key":"2023072819545488600_bib25","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1038\/nprot.2012.101","article-title":"Identifying ChIP-seq enrichment using MACS","volume":"7","author":"Feng","year":"2012","journal-title":"Nat. Protoc."},{"key":"2023072819545488600_bib26","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.immuni.2019.06.013","article-title":"Protein Amounts of the MYC Transcription Factor Determine Germinal Center B Cell Division Capacity","volume":"51","author":"Finkin","year":"2019","journal-title":"Immunity."},{"key":"2023072819545488600_bib27","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1084\/jem.186.3.439","article-title":"Disruption of the Bcl6 gene results in an impaired germinal center formation","volume":"186","author":"Fukuda","year":"1997","journal-title":"J. Exp. Med."},{"key":"2023072819545488600_bib28","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1101\/gr.127373.111","article-title":"Transposase mediated construction of RNA-seq libraries","volume":"22","author":"Gertz","year":"2012","journal-title":"Genome Res."},{"key":"2023072819545488600_bib29","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.1016\/j.immuni.2021.08.017","article-title":"Limited access to antigen drives generation of early B cell memory while restraining the plasmablast response","volume":"54","author":"Glaros","year":"2021","journal-title":"Immunity."},{"key":"2023072819545488600_bib30","doi-asserted-by":"crossref","unstructured":"Gustafsson, C., A.De Paepe, C.Schmidl, and R.Mansson. 2018. High-Throughput ChIPmentation: freely scalable, single day ChIPseq data generation from very low cell-numbers.bioRxiv (Preprint posted September 27, 2018)10.1101\/426957","DOI":"10.1101\/426957"},{"key":"2023072819545488600_bib31","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":"2023072819545488600_bib32","doi-asserted-by":"publisher","first-page":"13789","DOI":"10.1073\/pnas.0605944103","article-title":"Testing gene function early in the B cell lineage in mb1-cre mice","volume":"103","author":"Hobeika","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072819545488600_bib33","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1084\/jem.20171704","article-title":"Bhlhe40 is an essential repressor of IL-10 during Mycobacterium tuberculosis infection","volume":"215","author":"Huynh","year":"2018","journal-title":"J. Exp. Med."},{"key":"2023072819545488600_bib34","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1084\/jem.20161263","article-title":"The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help","volume":"214","author":"Inoue","year":"2017","journal-title":"J. Exp. Med."},{"key":"2023072819545488600_bib35","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1038\/ni.2037","article-title":"The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells","volume":"12","author":"Ise","year":"2011","journal-title":"Nat. Immunol."},{"key":"2023072819545488600_bib36","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/j.immuni.2018.03.027","article-title":"T Follicular Helper Cell-Germinal Center B Cell Interaction Strength Regulates Entry into Plasma Cell or Recycling Germinal Center Cell Fate","volume":"48","author":"Ise","year":"2018","journal-title":"Immunity."},{"key":"2023072819545488600_bib37","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":"2023072819545488600_bib38","doi-asserted-by":"publisher","first-page":"E3394","DOI":"10.1073\/pnas.1604178113","article-title":"Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-\u03b3 production in iNKT cells","volume":"113","author":"Kanda","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072819545488600_bib39","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abe6291","article-title":"Single-cell analysis of human B cell maturation predicts how antibody class switching shapes selection dynamics","volume":"6","author":"King","year":"2021","journal-title":"Sci. Immunol."},{"key":"2023072819545488600_bib40","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1038\/ni.3694","article-title":"Essential role for the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells","volume":"18","author":"Kreslavsky","year":"2017","journal-title":"Nat. Immunol."},{"key":"2023072819545488600_bib41","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/j.immuni.2008.04.014","article-title":"Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development","volume":"28","author":"Kwon","year":"2008","journal-title":"Immunity."},{"key":"2023072819545488600_bib42","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/s41586-018-0414-6","article-title":"RNA velocity of single cells","volume":"560","author":"La Manno","year":"2018","journal-title":"Nature."},{"key":"2023072819545488600_bib43","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods."},{"key":"2023072819545488600_bib44","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1016\/S1074-7613(01)00227-8","article-title":"A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival","volume":"15","author":"Lee","year":"2001","journal-title":"Immunity."},{"key":"2023072819545488600_bib45","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.immuni.2019.08.013","article-title":"The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8+ T Cell Fitness and Functionality","volume":"51","author":"Li","year":"2019","journal-title":"Immunity."},{"key":"2023072819545488600_bib46","doi-asserted-by":"publisher","first-page":"3551","DOI":"10.1038\/ncomms4551","article-title":"Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation","volume":"5","author":"Lin","year":"2014","journal-title":"Nat. Commun."},{"key":"2023072819545488600_bib47","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"2023072819545488600_bib48","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1111\/imm.12171","article-title":"Identification of co-expressed gene signatures in mouse B1, marginal zone and B2 B-cell populations","volume":"141","author":"Mabbott","year":"2014","journal-title":"Immunology."},{"key":"2023072819545488600_bib49","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1093\/bioinformatics\/btr189","article-title":"MEME-ChIP: motif analysis of large DNA datasets","volume":"27","author":"Machanick","year":"2011","journal-title":"Bioinformatics."},{"key":"2023072819545488600_bib50","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.immuni.2016.09.001","article-title":"Germinal Center B Cell Dynamics","volume":"45","author":"Mesin","year":"2016","journal-title":"Immunity."},{"key":"2023072819545488600_bib51","doi-asserted-by":"publisher","first-page":"7330","DOI":"10.4049\/jimmunol.1001381","article-title":"The role of the basic helix-loop-helix transcription factor Dec1 in the regulatory T cells","volume":"185","author":"Miyazaki","year":"2010","journal-title":"J. Immunol."},{"key":"2023072819545488600_bib52","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":"2023072819545488600_bib53","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1016\/j.immuni.2013.04.009","article-title":"Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4","volume":"38","author":"Ochiai","year":"2013","journal-title":"Immunity."},{"key":"2023072819545488600_bib54","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/ni.2242","article-title":"Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile","volume":"13","author":"Oestreich","year":"2012","journal-title":"Nat. Immunol."},{"key":"2023072819545488600_bib55","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1084\/jem.20030275","article-title":"Constitutive expression of AID leads to tumorigenesis","volume":"197","author":"Okazaki","year":"2003","journal-title":"J. Exp. Med."},{"key":"2023072819545488600_bib56","first-page":"317","article-title":"Stra13 and Sharp-1, the Non-Grouchy Regulators of Development and Disease","volume-title":"Current Topics in Developmental Biology.","author":"Ow","year":"2014"},{"key":"2023072819545488600_bib57","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp596","article-title":"Transcriptome analysis by strand-specific sequencing of complementary DNA","volume":"37","author":"Parkhomchuk","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023072819545488600_bib58","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/ng.2007.35","article-title":"AID is required for germinal center-derived lymphomagenesis","volume":"40","author":"Pasqualucci","year":"2008","journal-title":"Nat. Genet."},{"key":"2023072819545488600_bib59","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/nprot.2014.006","article-title":"Full-length RNA-seq from single cells using Smart-seq2","volume":"9","author":"Picelli","year":"2014","journal-title":"Nat. Protoc."},{"key":"2023072819545488600_bib60","doi-asserted-by":"publisher","first-page":"3130","DOI":"10.1038\/emboj.2012.155","article-title":"The B-cell identity factor Pax5 regulates distinct transcriptional programmes in early and late B lymphopoiesis","volume":"31","author":"Revilla-i-Domingo","year":"2012","journal-title":"EMBO J."},{"key":"2023072819545488600_bib61","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1016\/j.celrep.2020.01.009","article-title":"The amount of BCL6 in B cells shortly after antigen engagement determines their representation in subsequent germinal centers","volume":"30","author":"Robinson","year":"2020","journal-title":"Cell Rep"},{"key":"2023072819545488600_bib62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002762","article-title":"Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice","volume":"3","author":"Rossner","year":"2008","journal-title":"PLoS One."},{"key":"2023072819545488600_bib63","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1016\/j.immuni.2015.10.021","article-title":"PI3 Kinase and FOXO1 Transcription Factor Activity Differentially Control B Cells in the Germinal Center Light and Dark Zones","volume":"43","author":"Sander","year":"2015","journal-title":"Immunity."},{"key":"2023072819545488600_bib64","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nbt.3192","article-title":"Spatial reconstruction of single-cell gene expression data","volume":"33","author":"Satija","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"2023072819545488600_bib65","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1084\/jem.20102477","article-title":"A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center","volume":"208","author":"Schwickert","year":"2011","journal-title":"J. Exp. Med."},{"key":"2023072819545488600_bib66","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1038\/nrc3774","article-title":"The tumour microenvironment in B cell lymphomas","volume":"14","author":"Scott","year":"2014","journal-title":"Nat. Rev. Cancer."},{"key":"2023072819545488600_bib67","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1002\/eji.200324700","article-title":"Impaired lymphocyte development and function in Clast5\/Stra13\/DEC1-transgenic mice","volume":"34","author":"Seimiya","year":"2004","journal-title":"Eur. J. Immunol."},{"key":"2023072819545488600_bib68","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/S1074-7613(00)00020-0","article-title":"BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control","volume":"13","author":"Shaffer","year":"2000","journal-title":"Immunity."},{"key":"2023072819545488600_bib69","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/ni776","article-title":"Role of antigen receptor affinity in T cell-independent antibody responses in vivo","volume":"3","author":"Shih","year":"2002","journal-title":"Nat. Immunol."},{"key":"2023072819545488600_bib70","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1016\/0092-8674(92)90029-C","article-title":"RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement","volume":"68","author":"Shinkai","year":"1992","journal-title":"Cell."},{"key":"2023072819545488600_bib71","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/1471-213X-1-4","article-title":"Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus","volume":"1","author":"Srinivas","year":"2001","journal-title":"BMC Dev. Biol."},{"key":"2023072819545488600_bib72","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":"2023072819545488600_bib73","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell."},{"key":"2023072819545488600_bib74","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1016\/j.immuni.2017.11.022","article-title":"CCR6 Defines Memory B Cell Precursors in Mouse and Human Germinal Centers, Revealing Light-Zone Location and Predominant Low Antigen Affinity","volume":"47","author":"Suan","year":"2017","journal-title":"Immunity."},{"key":"2023072819545488600_bib75","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072819545488600_bib76","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1038\/ni721","article-title":"Defective T cell activation and autoimmune disorder in Stra13-deficient mice","volume":"2","author":"Sun","year":"2001","journal-title":"Nat. Immunol."},{"key":"2023072819545488600_bib77","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1016\/j.it.2012.07.005","article-title":"Heterogeneity in the differentiation and function of memory B cells","volume":"33","author":"Taylor","year":"2012","journal-title":"Trends Immunol."},{"key":"2023072819545488600_bib78","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1084\/jem.20111696","article-title":"A germinal center-independent pathway generates unswitched memory B cells early in the primary response","volume":"209","author":"Taylor","year":"2012","journal-title":"J. Exp. Med."},{"key":"2023072819545488600_bib79","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1093\/bioinformatics\/btp120","article-title":"TopHat: discovering splice junctions with RNA-Seq","volume":"25","author":"Trapnell","year":"2009","journal-title":"Bioinformatics."},{"key":"2023072819545488600_bib80","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/0092-8674(94)90321-2","article-title":"Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells","volume":"77","author":"Turner","year":"1994","journal-title":"Cell."},{"key":"2023072819545488600_bib81","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/nature03555","article-title":"A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity","volume":"435","author":"Vinuesa","year":"2005","journal-title":"Nature."},{"key":"2023072819545488600_bib82","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1007\/s12064-012-0162-3","article-title":"Measurement of mRNA abundance using RNA-seq data: RPKM measure is inconsistent among samples","volume":"131","author":"Wagner","year":"2012","journal-title":"Theory Biosci."},{"key":"2023072819545488600_bib83","doi-asserted-by":"publisher","first-page":"3200","DOI":"10.4049\/jimmunol.1303216","article-title":"Transcription factor IRF4 regulates germinal center cell formation through a B cell-intrinsic mechanism","volume":"192","author":"Willis","year":"2014","journal-title":"J. Immunol."},{"key":"2023072819545488600_bib84","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1016\/j.cell.2013.08.022","article-title":"One-step generation of mice carrying reporter and conditional alleles by CRISPR\/Cas-mediated genome engineering","volume":"154","author":"Yang","year":"2013","journal-title":"Cell."},{"key":"2023072819545488600_bib85","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/ng0697-161","article-title":"The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation","volume":"16","author":"Ye","year":"1997","journal-title":"Nat. Genet."},{"key":"2023072819545488600_bib86","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1016\/j.cell.2018.12.036","article-title":"The cis-Regulatory Atlas of the Mouse Immune System","volume":"176","author":"Yoshida","year":"2019","journal-title":"Cell."},{"key":"2023072819545488600_bib87","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":"2023072819545488600_bib88","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1084\/jem.20170155","article-title":"The transcription factor Bhlhe40 is a switch of inflammatory versus antiinflammatory Th1 cell fate determination","volume":"215","author":"Yu","year":"2018","journal-title":"J. Exp. Med."},{"key":"2023072819545488600_bib89","doi-asserted-by":"publisher","first-page":"14049","DOI":"10.1038\/ncomms14049","article-title":"Massively parallel digital transcriptional profiling of single cells","volume":"8","author":"Zheng","year":"2017","journal-title":"Nat. Commun."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20211406\/1839796\/jem_20211406.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20211406\/1839796\/jem_20211406.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T15:56:46Z","timestamp":1690559806000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/219\/2\/e20211406\/212923\/Bhlhe40-function-in-activated-B-and-TFH-cells"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,17]]},"references-count":89,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2,7]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20211406","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.03.12.435122","asserted-by":"object"}]},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,17]]},"article-number":"e20211406"}}