ArticlebioRxiv : the preprint server for biology2025
Notch2 signaling instructs viral and bacterial TLR responsiveness in B cells.
Jennifer Londregan, Isaiah Rozich, Brian T Gaudette, Nicholas J Tursi, David B Weiner, Ivan Maillard, David Allman
Abstract readPreprint
In one paragraphArticle in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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2 · The registryThe trial behind it
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4 · The recordCorrections and comments
5 · Who and what moneyAuthors and funding
7 authors.
Jennifer LondreganDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-6082, USA.ORCID 0000-0003-2236-3577 Isaiah RozichDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-6082, USA.
Brian T GaudetteCleveland Clinic Lerner College of Medicine of Case Western Reserve University, USA.
Nicholas J TursiDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-6082, USA.
David B WeinerVaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.
Ivan MaillardDivision of Hematologic Malignancies, Department of Medicine & Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
David AllmanDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-6082, USA.
Funding
COLLABORATIVE INFLUENZA VACCINE INNOVATION CENTER: UNIVERSAL INFLUENZA VACCINE RESEARCH75N93019C00051 · NIAID · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI KRAMMER, FLORIAN · 2019 to 2025
$105.4MTRAINING PROGRAM IN BASIC CANCER RESEARCHT32CA009171 · NCI · WISTAR INSTITUTE · PI Alessandro Gardini · 1985 to 2026
$15.3MTRAINING IN HIV PATHOGENESIST32AI007632 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI Frederic D Bushman, James L. Riley · 2000 to 2026
$10.6MNotch Signaling in AlloimmunityR01AI091627 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI PEAR, WARREN S · 2011 to 2025
$6.0MStructural vaccinology guided development of a universal CoV vaccine utilizing nucleic acid delivered nanoparticlesP01AI165066 · NIAID · WISTAR INSTITUTE · PI Jesper Pallesen, DAVID B. WEINER · 2022 to 2026
$5.3MBiochemical Mechanisms for Sustained Humoral ImmunityR01AI175185 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI David M Allman · 2023 to 2026
$2.5MNotch ligands as oncogenic drivers and therapeutic targets in T-cell lymphomasR01CA278976 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Ivan Maillard, Ryan A Wilcox · 2024 to 2026
$1.9MThe Notch Pathway in Antigen DesignR21AI174069 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI ALLMAN, DAVID M · 2023 to 2024
$472kNotch2 Amplification of B Cell Division and Differentiation FatesF31AI179166 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI LONDREGAN, JENNIFER · 2024 to 2025
$74kNCI NIH HHS R01 CA278976NCI NIH HHS T32 CA009171NIAID NIH HHS 75N93019C00051NIAID NIH HHS F31 AI179166NIAID NIH HHS P01 AI165066NIAID NIH HHS R01 AI091627NIAID NIH HHS R01 AI175185NIAID NIH HHS R21 AI174069NIAID NIH HHS T32 AI007632
6 · The paper itselfAbstract
Marginal zone (MZ) B cells are hyperresponsive to bacterial Toll-like Receptor (TLR) ligands. However, the full extent of TLR responsiveness for MZ B cells and the mechanisms regulating such responses are unclear. We report that Notch2 activation establishes MZ B cell responsiveness for the viral dsRNA receptor TLR3 and augments responses for the LPS receptor TLR4. Notch2 ligation accelerated Myc induction, mitosis, and plasma cell differentiation to LPS. Further, TLR3 expression in MZ B cells was Notch2 dependent, and ectopic Notch2 signaling was sufficient to promote robust TLR3 responsiveness dependent on the TIR-domain-containing adapter TRIF and the kinase BTK. TLR3 engagement in MZ B cells promoted proliferation, differentiation, and the secretion of IgG2b and IgG2c antibodies. Our results establish a novel role for Notch2 in establishing TLR3 and TLR4 responsiveness in B cells and suggest that MZ B cells play unappreciated roles in immunity against RNA viruses.
Identifiers
PMID41279825
PMCPMC12632369
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