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Peer-reviewedCC BY-NCCell reports

Notch2 signaling instructs viral and bacterial TLR responsiveness in B cells

  • Jennifer Londregan1
  • Isaiah Rozich1
  • Brian T. Gaudette2
  • Jeffrey R. Maslanka3
  • Rachel Serafin3
  • Nicholas J. Tursi4
  • Sarah Naiyer1
  • Scott E. Hensley3
  • David B. Weiner4
  • Ivan Maillard5
  • David Allman1,6
6 affiliations
  1. 1Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia PA 19104-6082, USA.
  2. 2Department of Inflammation & Immunity, Cleveland Clinic Research, Cleveland, OH, 44195, USA.
  3. 3Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104-6082, USA.
  4. 4Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia PA 19104-6082, USA.
  5. 5Department of Medicine & Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  6. 6Lead contact
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{londregan2026notch2,
  title = {{Notch2 signaling instructs viral and bacterial TLR responsiveness in B cells}},
  author = {Jennifer Londregan and Isaiah Rozich and Brian T. Gaudette and Jeffrey R. Maslanka and Rachel Serafin and Nicholas J. Tursi and Sarah Naiyer and Scott E. Hensley and David B. Weiner and Ivan Maillard and David Allman},
  journal = {Cell reports},
  year = {2026},
  month = jul,
  doi = {10.1016/j.celrep.2026.117748},
  url = {https://doi.org/10.1016/j.celrep.2026.117748},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Notch2 signaling instructs viral and bacterial TLR responsiveness in B cells
AU  - Jennifer Londregan
AU  - Isaiah Rozich
AU  - Brian T. Gaudette
AU  - Jeffrey R. Maslanka
AU  - Rachel Serafin
AU  - Nicholas J. Tursi
AU  - Sarah Naiyer
AU  - Scott E. Hensley
AU  - David B. Weiner
AU  - Ivan Maillard
AU  - David Allman
PY  - 2026
DA  - 2026/07/30
JO  - Cell reports
DO  - 10.1016/j.celrep.2026.117748
UR  - https://doi.org/10.1016/j.celrep.2026.117748
AB  - 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.
SN  - 2211-1247
ER  -