A single human VH gene endows for a broad-spectrum antibody response targeting bacterial lipopolysaccharides in the blood
B cell receptors (BCRs) display a combination of variable (V) gene-encoded complementarity determining regions (CDRs) and adaptive/hypervariable CDR3 loops to engage antigens. It has long been proposed that the former naturally tune for recognition of pathogens or groups of pathogens. To mechanistically evaluate this within the human antibody repertoire, we performed immune challenges in transgenic mice bearing diverse human CDR3 and light chains, but were constrained to different human VH genes. We found that out of six commonly deployed VH sequences, only those CDRs encoded by IGHV1-2*02 enabled polyclonal antibody responses against bacterial lipopolysaccharide (LPS) when introduced to the bloodstream. LPS was prepared from diverse strains of gram-negative bacteria, and the VH gene-dependent responses were directed against the non-variable and universal saccrolipid substructure of this antigen. This reveals a broad-spectrum anti-LPS response in which germline-encoded CDRs naturally hardwire the human antibody repertoire for recognition of a conserved microbial target. Overall design: Examination of antibody CDRH3 diversity within transgenic mice restricted to human IGHV1-69 or human IGHV1-2 VH genes and containing the human IgK locus.