T-bet+ Memory B Cells Link to Local Cross-Reactive IgG upon Human Rhinovirus Infection

Abstract

Summary: Human rhinoviruses cause the common cold and exacerbate chronic respiratory diseases. Although infection elicits neutralizing antibodies, these do not persist or cross-protect across multiple rhinovirus strains. To analyze rhinovirus-specific B cell responses in humans, we developed techniques using intact RV-A16 and RV-A39 for high-throughput high-dimensional single-cell analysis, with parallel assessment of antibody isotypes in an experimental infection model. Our approach identified T-bet+ B cells binding both viruses that account for ∼5% of CXCR5− memory B cells. These B cells infiltrate nasal tissue and expand in the blood after infection. Their rapid secretion of heterotypic immunoglobulin G (IgG) in vitro, but not IgA, matches the nasal antibody profile post-infection. By contrast, CXCR5+ memory B cells binding a single virus are clonally distinct, absent in nasal tissue, and secrete homotypic IgG and IgA, mirroring the systemic response. Temporal and spatial functions of dichotomous memory B cells might explain the ability to resolve infection while rendering the host susceptible to re-infection. : Eccles et al. demonstrate a key role for T-bet+ B cells in rapid local cross-reactive immunoglobulin G (IgG) responses to rhinovirus, whereas strain-specific B cells that are phenotypically distinct match systemic antibodies found later. This might explain efficient clearance of virus in the acute phase but narrow protection and continued susceptibility after the infection clears. Keywords: rhinovirus, adaptive immunity, B cells, T-bet, CXCR5, IgG, IgA, cross-reactivity, Human, Mass cytometry