Old hematopoietic stem cells retain competence to reconstitute a youthful B cell system that is highly responsive to protein-based vaccination

BACKGROUND: Ageing-associated remodeling of the murine B cell system is accompanied with a reduction of CD19(+) B cells such as follicular B cells (FOB) and an accumulation of age-associated B cells (ABC) or activated B cell subsets. This remodeling is thought to confer an attenuated antibody response, such as to SARS-CoV-2 spike (S) vaccines in both aged mice and humans. To gain insight into the de novo development and function of an old B cell system, we reconstituted young and old immune systems by transferring hematopoietic stem cells (HSCs) from immune-competent young (2-3 months) CD45.1(+) donors (DY-HSC) or old (20-24 months) donors (DO-HSC) into T and B cell-deficient young recipient CD45.2(+) RAG1(-/-) mice, followed by protein-based vaccination. RESULTS: In the same environment of young RAG1(-/-) mice, transplanted DO-HSCs compared to DY-HSCs reconstituted lower numbers of CD19(+) B cells and CD45.1(+) cells, though the engraftment of donor-derived HSCs in the young bone marrow (BM) was very similar. Furthermore, indicative for youthful and unchallenged B cell systems, and in contrast to aged mice, very low levels of antigen-experienced memory B cells or age-associated B cells (ABC) developed in both DY-HSC and DO-HSC hosts. The commercially available recombinant SARS-CoV-2 S vaccine (NVX-CoV2373) induced lower IgG(+) S-antibody titers and pseudovirus neutralization activity in old compared to young mice. In contrast, very similar high IgG(+) S-antibody titers were induced in DO-HSC and DY-HSC hosts, and pseudovirus neutralization activity was even enhanced in DO-HSC compared with DY-HSC hosts. CONCLUSIONS: Both DO-HSCs and DY-HSCs established in the young recipient BM to a similar extend, suggesting that the concomitant reduction in the de novo reconstitution of CD19(+) B cells in DO-HSC vs. DY-HSC transplanted animals is specifically related to old HSCs. DO-HSCs and DY-HSCs reconstitute very similar unchallenged B cell systems that efficiently elicit antigen-specific IgG antibodies by protein-based vaccination. Old HSCs thus retain competence to reconstitute a youthful and functional B cell system, at least in the young environment of transplanted RAG1(-/-) mice. This suggests that it is primarily age-related factors, and not HSCs per se, that influence the composition and functionality of the old B cell system.