Pan-isotype long-lived plasma cells: origins, diversity, and specificity

Abstract

Antibody titers can remain stable for years due to the establishment of long-lived plasma cells in the bone marrow. However, these cells remain poorly characterized in humans, and the full extent of their origin, cellular diversity, and antigenic specificity is not fully understood. In this work, we provide an in-depth characterization of plasma cell diversity. Using complementary approaches based on both human samples and murine models, we show that long-lived bone marrow plasma cells exhibit transcriptional heterogeneity relative to core cellular functions associated with protein metabolism. We show that patterns of somatic hypermutation and intra-clonal antibody sequence diversity can be used to infer cellular origin of antibody-secreting cells. In humans, surface CD19 expression on plasma cell was correlated with increased frequency of somatic hypermutation in antibody genes, further suggesting differential cellular ancestry. Considering the persistence of IgE antibody titers in people with food allergies despite the rarity of circulating IgE-secreting plasma cells, we turned our attention to IgE bone marrow plasma cells. These cells were enriched in the bone marrow of people with food allergies compared to non-allergic controls, showed signs of endoplasmic reticulum stress and enhanced protein production, and encoded antibodies that target food allergens. These results suggest that bone marrow plasma cells may contribute to sustaining anti-allergen IgE antibody titers over time. Finally, we show that, contrary to a core tenet of humoral immunology, initial antigen recognition is not required for the generation of plasma cell responses in the setting of low B cell competition in mice. We conclude that both antigen recognition and cellular ancestry shape plasma cell generation, diversity, and longevity. Our results highlight the underappreciated diversity in the plasma cell compartment and have implications on vaccine design and immunotherapeutic development.