Notch2 signaling instructs viral and bacterial TLR responsiveness in B cells.
Marginal zone (MZ) B cells optimize protection against blood-borne bacteria by rapidly producing plasma cells in response to Toll-like receptor (TLR) ligands. Here, we demonstrate that Notch2 instructs this responsiveness for both the dsRNA sensor TLR3 and LPS sensor TLR4. Using mathematical modeling of cell trace time-course data, we reveal that constitutive Notch2 experience affords lipopolysaccharide (LPS) hyperresponsiveness in Notch2-independent follicular B cells. This resulted in earlier Myc induction and accelerated cell cycle entry, ultimately augmenting division kinetics. Further, Notch2 engagement drove TLR3 expression and instructed an otherwise absent TLR3 response program, dependent on both the TIR-domain-containing-adaptor, TRIF and the kinase BTK. Access to Notch2 ligands instructed a T-independent plasma cell differentiation program. We conclude that Notch2 controls several aspects of TLR3 and TLR4 function in B cells and further suggest that MZ B cells may play previously unappreciated roles in immunity against RNA viruses.