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

Abstract

Abstract Maturation of an antibody response entails somatic hypermutation (SHM), class-switch DNA recombination (CSR), plasma cell differentiation and generation of memory B cells, and 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 flagellin induced specific, mature antibody responses in Tcrβ −/−Tcrδ −/−mice and in NSG/B mice (B cells only). Such coengagement requires physical linkage of TLR and BCR ligands, “linked coengagement”, which induced germinal center-like differentiation, clonal expansion, CSR/SHM, intraclonal diversification, plasma cell differentiation, TLR expression, production of specific antibodies and generation of memory B cells supporting anamnestic antibody responses, overall indicating an affinity maturation process. In Tcrβ −/−Tcrδ −/−mice, linked coengagement of TLR4 and cognate BCR by LPS (Lipid A and polysaccharidic O-antigen) or TLR5 and cognate BCR by flagellin induced neutralizing and protective antibodies to E. coli or S. Typhimurium, limiting infection and pathology. Intrinsic B cell TLR-BCR linked coengagement likely plays an important role in inducting mature and neutralizing antibody responses in the absence of T cells. It would also play an important role in early stages of T-dependent anti-microbial responses when T cell help is not yet available, as well as potentiate the late-stage response when T help is available. Finally, it may inform the development of B cell TLR-based vaccines to microbial pathogens, particularly for subjects with an immature T cell compartment, such as the infant, or declining T cell function and clonality, such as the elderly. Supported by NIH grants AI 079705, AI 105813/105813S1, AI138944, AI 167416 and Lupus Research Alliance grant LRA 641363 to PC and PHS grant K12 GM111726.