Defining Memory B-cell Responses to Human Rhinovirus Infection

Rhinoviruses, which account for the majority of cases of common cold, arguably cause more frequent illness in humans than any other pathogen. Despite this, relatively little is known about B-cell and humoral responses to this ubiquitous virus, and in particular, about the failure of infection to induce durable immunity to multiple rhinovirus strains. Here, we aimed to rigorously elucidate these processes, and in doing so we revealed a novel B-cell subset endowed with a unique advantage in viral clearance. Specifically, we found that IgG-restricted B-cells that lack the chemokine receptor CXCR5 express a molecular signature consistent with effector memory, and secrete antibodies that cross-react with different rhinovirus strains, whereas lymphotropic memory cells that express CXCR5 typically target only a single strain. High-dimensional phenotyping by mass cytometry identified a novel dual-specific B-cell “effector memory” subset that expressed the transcription factor T-bet, consistent with an “age-associated” signature. These cells were able to secrete cross-reactive IgG more rapidly compared with their mono-specific counterparts, expanded in vivo in the blood of infected humans after acute infection, and their phenotype mirrored cell bodies and secreted antibodies detected in the acutely infected nose. The kinetics and quality of serum antibody profiles coupled with cellular fluxes during infection also implied a link between serum antibody responses that lack cross-reactive activity and mono-specific memory B-cells. Our results suggest that B-cell recall responses to rhinovirus efficiently clear infection, but fail to provide long-term protection against heterotypic strains, based on the dogma that long-lived plasma cells derive from conventional CXCR5+ memory. These findings query the respective lineages of B-cells that resemble central memory and effector memory phenotypes, and how they acquire and recognize antigen. We propose that harnessing the attributes of cross-reactive memory B-cells might provide an opportunity for inducing durable cross-protective immunity against this troublesome virus.