{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:21Z","timestamp":1792790301102,"version":"4.5.0"},"posted":{"date-parts":[[2026,6,19]]},"group-title":"Immunology","reference-count":75,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIAID","award":["U01AI141990"],"award-info":[{"award-number":["U01AI141990"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIAID","award":["RO1AI145064"],"award-info":[{"award-number":["RO1AI145064"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIAID","award":["5T32AI089443"],"award-info":[{"award-number":["5T32AI089443"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The transcription factors IRF4 and BLIMP1 (\n                  <jats:italic>PRDM1<\/jats:italic>\n                  ) promote plasma cell (PC) differentiation by repressing B cell identity genes while inducing the unfolded protein response, ER\/Golgi biogenesis, and immunoglobulin secretion. How IRF4 and BLIMP1 partition and coordinate their genomic activities during plasma cell differentiation remains unresolved. Using na\u00efve human B cells and a stepwise\n                  <jats:italic>in vitro<\/jats:italic>\n                  differentiation system, we performed CRISPR\/Cas9 perturbations of\n                  <jats:italic>IRF4<\/jats:italic>\n                  or\n                  <jats:italic>PRDM1<\/jats:italic>\n                  in activated B-lineage cells that contained demonstrable plasma cell precursors, followed by single-cell RNA sequencing. Despite their mutually reinforced expression and shared recognition of related IRF-family motifs (ISREs and EICEs), loss of IRF4, but not of BLIMP1, yielded a stunted intermediate with incomplete silencing of B cell identity genes and defective induction of the secretory program. Multiome profiling, base-pair-resolution motif modeling, CUT&amp;RUN, and DNA-binding assays identified non-conserved nucleotides within ISRE\/EICE motifs that discriminate IRF4 from BLIMP1 binding. These findings define an ISRE\/EICE motif lexicon that predicts differential IRF4 and BLIMP1 occupancy and are consistent with a temporally ordered model, in which IRF4 first acts independently and then in concert with BLIMP1 to promote PC differentiation.\n                <\/jats:p>","DOI":"10.64898\/2026.06.15.732353","type":"posted-content","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T17:25:22Z","timestamp":1781889922000},"source":"Crossref","is-referenced-by-count":0,"title":["Sequential and coordinated control of human plasma cell differentiation by IRF4 and BLIMP1 associated with a discriminating ISRE\/EICE motif lexicon"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8547-5923","authenticated-orcid":false,"given":"Louis C.","family":"Lau","sequence":"first","affiliation":[{"name":"Center for Systems Immunology and Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sneha","family":"Lal","sequence":"additional","affiliation":[{"name":"Center for Systems Immunology and Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Fan","sequence":"additional","affiliation":[{"name":"Center for Systems Immunology and Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6140-1949","authenticated-orcid":false,"given":"Nicholas A.","family":"Pease","sequence":"additional","affiliation":[{"name":"Center for Systems Immunology and Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6330-8526","authenticated-orcid":false,"given":"Harinder","family":"Singh","sequence":"additional","affiliation":[{"name":"Center for Systems Immunology and Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100817501211000_2026.06.15.732353v2.1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023023237"},{"key":"2026100817501211000_2026.06.15.732353v2.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.2.553"},{"key":"2026100817501211000_2026.06.15.732353v2.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.11.5046"},{"key":"2026100817501211000_2026.06.15.732353v2.4","doi-asserted-by":"publisher","DOI":"10.1101\/gad.10.18.2335"},{"key":"2026100817501211000_2026.06.15.732353v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33787-8"},{"key":"2026100817501211000_2026.06.15.732353v2.6","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131831"},{"key":"2026100817501211000_2026.06.15.732353v2.7","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103720"},{"key":"2026100817501211000_2026.06.15.732353v2.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.115977"},{"key":"2026100817501211000_2026.06.15.732353v2.9","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2006"},{"key":"2026100817501211000_2026.06.15.732353v2.10","doi-asserted-by":"publisher","DOI":"10.1093\/jimmun\/vkaf354"},{"key":"2026100817501211000_2026.06.15.732353v2.11","unstructured":"Delphine Charif, O. 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