Studies performed in a germinal center fate mapping mouse reporter line have led to the unanticipated discovery of a large IgM+ memory subset, which arises spontaneously in the spleen in the absence of any external challenge and is maintained through constant output from gut mucosal responses. This subset present reactivity against bacterial epitopes, possibly glycan structures (Le Gallou et al., 2018). This observation makes a link with our study of human anti-polysaccharide responses, suggesting that such responses may capitalize upon previous B-cell activation by gut microbial antigens, rather than mobilizing naive B cells.
In collaboration with the group of Daniel Pinschewer (Basel University), we described that chronic viral infection in the mouse, while it leads to exhaustion of cytotoxic T cell responses, is able to generate protracted germinal centers from which B cells secreting neutralizing antibodies will be able to emerge (Fallet et al., 2020). Finally, we also identified in the mouse key factors that favor affinity maturation over plasma cell differentiation of memory cells during recall responses, notably persistent germinal center structures and waning antigen-specific serum antibodies.
Concerning long-lived memory B cells in humans, transcriptional studies performed at the single cell level did not reveal major transcriptional changes compared to the global memory population of the same individual, although telomere length clearly establish the anteriority of smallpox-specific memory B cell formation. Metabolomic studies, transcriptomic and ATAC-seq studies identified a Notch-dependent resident signature which, surprisingly is shared by a major fraction of memory B cells, clearly indicating that longevity is the hallmark of most immune memories elicited during immune responses.
A cohort of volunteers has been immunized with Pneumo23, a 23-valent pneumococcal polysaccharide vaccine, and their blood response followed up to 2 months. High throughput sequencing of the immune repertoire has been performed and revealed, as mentioned above, the surprising mobilization of pre-diversified B cells against non-protein antigens. Isolation of anti-pneumococcal antibodies allowed us to identify a fraction of the gut microbiota recognized by these antibodies, suggesting that this pre-diversification of marginal zone B cells takes place in gut-associated lymphoid tissues. In parallel, emergence of marginal zone-like human B cells was observed in a new humanized mouse model that is able to support the development of lymphoid tissue in the gut, strengthening the link between immune diversification in the gut and the capacity of Marginal-zone B cells to respond to polysaccharide antigens.
The fourth subject addressed since 2020 was the study of the B cell response against SARS-Cov-2, based on the longitudinal follow-up of a cohort of patients with Covid-19: this study described a first wave of activation and differentiation into antibody-secreting cells of naive B cells as well as crossreactive B cells that recognize seasonal coronaviruses, responsible of common cold, followed by a phase of germinal-center reactions lasting for several months during which memory B cells with better recognition for the spike protein of the SARS-Cov-2 are selected. In a second study, the response to mRNA vaccine was studied in Covid19 recovered and naive individuals, highlighting a strong difference in serum neutralization potency against virus variants between naive and recovered individuals. Memory B cells from naive individuals, in contrast, although numerically less abundant, showed a good neutralization potential, indicating that a booster dose will lead to their efficient mobilization and the production of protective serum antibodies in all cases.
