Somatic diversity in CDR3 loops allows single V-genes to encode innate immunological memories for multiple pathogens

Area of Science:

• Immunology
• Molecular Biology
• Microbiology

Background:

• Human antibody (Ab) responses to pathogens often involve limited immunoglobulin (Ig) V-genes.
• The IGVK3-11 and IGVH3-30 V-genes are frequently found in protective antibodies against Streptococcus pneumoniae (23F polysaccharide) and human cytomegalovirus (CMV) gB protein.

Purpose of the Study:

• To investigate the role of germline IGVK3-11 and IGVH3-30 V-genes in antibody binding and function.
• To determine if these germline V-genes can encode protective antibodies against distinct antigens.

Main Methods:

• Constructed IgGs using germline IGVK3-11 and IGVH3-30 V-genes with specific CDR3 sequences from a hypermutated anti-23F antibody.
• Assessed antibody binding specificity to 23F pneumococcal polysaccharides and L-rhamnose.
• Evaluated complement-dependent phagocytosis of S. pneumoniae by human neutrophils.

Main Results:

• Germline V-gene encoded IgGs specifically bound 23F polysaccharides and L-rhamnose, with no cross-reactivity to other glycans or pneumococcal serotypes.
• These antibodies mediated complement-dependent phagocytosis of encapsulated 23F S. pneumoniae.
• Mutations in CDRL3 and CDRH3 significantly impacted antibody binding.

Conclusions:

• The IGKV3-11 and IGHV3-30 V-genes, when recombined with specific CDR3 sequences, can encode binding sites for protective antibodies against diverse antigens.
• These V-genes may contribute to innate immunological memory against S. pneumoniae and human CMV.