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.
Jennifer Londregan, Isaiah Rozich, Brian T. Gaudette et al.· Cell Reports· 0 citations
For rapidly mutating viruses such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), immune memory recalled by antigenically drifted variants primarily comprises antibodies that cross-react to the priming strain rather than de novo elicited responses, a phenomenon termed original antigenic sin or immune imprinting. The composition and functionality of de novo responses elicited by variant exposures remain unclear. Here we isolated and characterized hundreds of recall and de novo neutralizing monoclonal antibodies after sequential exposures to SARS-CoV-2 variants in ancestral-imprinted humans. De novo variant type-specific antibodies used different V(D)J genes that were closer to germline sequence, potently neutralized future variants and targeted distinct receptor binding domain epitopes compared to ancestral cross-reactive (recall) antibodies. Nevertheless, neutralizing responses to the updated 2024–2025 booster were predominantly ancestral cross-reactive. These results reveal the distinct contributions of recall and de novo antibodies to a balanced immune response and underscore the benefit of updated booster vaccines, which augment both subsets. Updated SARS-CoV-2 boosters broaden humoral immunity by recalling cross-reactive antibodies and eliciting new less cross-reactive Omicron type-specific antibodies that target distinct RBD epitopes and more potently neutralize recent variants.
T. Johnston, S. Li, M. Painter et al.· Nature Immunology· 2 citations
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