Memory B Cells that Cross-React with Group 1 and Group 2 Influenza A Viruses Are Abundant in Adult Human Repertoires

• Published in: Immunity (Cambridge, Mass.) Vol. 48; no. 1; pp. 174 - 184.e9
• Main Authors: McCarthy, Kevin R., Watanabe, Akiko, Kuraoka, Masayuki, Do, Khoi T., McGee, Charles E., Sempowski, Gregory D., Kepler, Thomas B., Schmidt, Aaron G., Kelsoe, Garnett, Harrison, Stephen C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.01.2018; Elsevier Limited
• Subjects: Adult; Adults; Affinity; Antibodies; Antibodies, Viral - immunology; Antigens; B cell repertoire; B-Lymphocytes - immunology; Binding sites; Cell Culture Techniques; clonal selection; Complementarity; convergent evolution; Cross Reactions - immunology; Evolution & development; Exposure; Female; Flow Cytometry; Hemagglutinins; Hemagglutinins, Viral - immunology; Humans; Immunization; Immunoglobulins; Immunological memory; Infections; Influenza; Influenza A; Influenza A virus - immunology; influenza hemagglutinin; Interferometry; Lymphocytes B; Male; Memory; Memory cells; Orthomyxoviridae; Viruses; Washington DC; United States > US; B cell repertoire; clonal selection; influenza hemagglutinin; convergent evolution
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2017.12.009

Human B cell antigen-receptor (BCR) repertoires reflect repeated exposures to evolving influenza viruses; new exposures update the previously generated B cell memory (Bmem) population. Despite structural similarity of hemagglutinins (HAs) from the two groups of influenza A viruses, cross-reacting antibodies (Abs) are uncommon. We analyzed Bmem compartments in three unrelated, adult donors and found frequent cross-group BCRs, both HA-head directed and non-head directed. Members of a clonal lineage from one donor had a BCR structure similar to that of a previously described Ab, encoded by different gene segments. Comparison showed that both Abs contacted the HA receptor-binding site through long heavy-chain third complementarity determining regions. Affinities of the clonal-lineage BCRs for historical influenza-virus HAs from both group 1 and group 2 viruses suggested that serial responses to seasonal influenza exposures had elicited the lineage and driven affinity maturation. We propose that appropriate immunization regimens might elicit a comparably broad response. [Display omitted] •Human Bmem cells were found with BCRs cross-reactive for influenza A groups 1 and 2•Cross-group Bmem cells were abundant, unlike cross-group serum antibodies•Structures of HA receptor-site directed, cross-group antibodies showed key contacts•Cross-group lineage antibodies were similar to a genetically unrelated antibody Hemagglutinins (HAs) from the two influenza A subtype groups have similar structures, but cross-reacting serum antibodies are rare. McCarthy et al. nonetheless found, in three donors, abundant cross-group B cell receptors (BCRs), many with epitopes on the HA head. Members of one clonal lineage had a BCR structure similar to that of a previously described, genetically unrelated antibody. Serial responses to seasonal influenza appear to have elicited the lineage and driven affinity maturation. Appropriate immunization regimens might elicit comparable responses.