Intrinsic B cell TLR-BCR linked coengagement induces class-switched, hypermutated, neutralizing antibody responses in absence of T cells. Mus musculus

The maturation of an antibody response entails somatic hypermutation (SHM), class-switch DNA recombination, (CSR), plasma cell differentiation and generation of memory B cells, and it is thought to be generally dependent on T cell help. We show here that B cell TLR4-BCR (B cell receptor for antigen) coengagement by NP-LPS (from E. coli) or TLR5-BCR coengagement by Salmonella Typhimurium flagellin induced mature antibody responses to NP and flagellin in TCRb TCRd KO mice and in NSG/B mice (devoid of all immune cells and grafted with purified B cells). B cell TLR-BCR coengagement requires physical linkage of TLR and BCR ligands. Intrinsic B cell TLR-BCR linked coengagement induced B cell germinal center-like differentiation, clonal expansion with CSR and SHM-mediated intraconal diversification, plasma cell differentiation, TLR expression and generation of memory B cells mediating anamnestic antibody responses, indicating an antibody affinity maturation process. In TCRbTCRd KO mice, linked coengagement of TLR4 and cognate BCR by LPS (Lipid A and polysaccharidic O-antigen moieties) and linked coengagement of TLR5 and cognate BCR by flagellin induced antibodies that neutralize E. coli and S. Typhimurium, leading to reduced infection and pathology. Overall, our findings unveiled an unappreciated role of B cell TLRs in induction of specific, mature and neutralizing antibody responses without T cell help. B cell TLR-BCR linked coengagement likely represents an evolutionary conserved mechanism, one that would also play an important role in early stages of T-dependent anti-microbial responses when T cell help is not yet available, or in subjects with an immature or defective T compartment, such as the infant and the elderly.