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Integrated single cell multiomic profiling and functional validation reveal distinct cellular routes to human plasma cell differentiation.

ABSTRACT: Upon activation, B cells undergo profound transcriptional, epigenetic, and metabolic reprogramming to form antibody secreting plasma cells bearing little resemblance to their progenitors. Here, we used single cell RNA and ATAC sequencing of primary and in vitro differentiating human B cells to identify multiple distinct plasma cell subsets and differentiation routes depending on the starting cell type. In primary tonsils, we observed two distinct plasma cell subsets distinguished by expression of CD44 variant 9 (CD44v9), CD38, CD31, and CD10. A transient and rare CD30+ intermediate was identified both in primary tonsils and in vitro. CD40, TLR9, and cytokine stimulation of naïve and memory B cells formed CD30+ cells, which then formed plasma cells that were exclusively CD44v9+. CD30+ intermediates were not generated from primary germinal center B cells as they differentiated into plasma cells, which mostly lacked expression of CD44v9. Analysis of single cell multiomic data and pharmacological inhibition experiments demonstrated that the CD30+ intermediate was promoted by the transcription factor MEF2C. BAFF and APRIL promoted further maturation of these cells to CD44v9+ plasma cells. These data suggest that human germinal center-independent and -dependent ontogenies are biased towards distinct differentiation routes and terminal plasma cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318326 | GEO | 2026/02/09

REPOSITORIES: GEO

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Project description:CD30L and CD30 are cell-surface glycoproteins in the TNF and TNFR superfamilies, respectively. Their expression is limited to immune cells and is tightly regulated. Cell surface expression of CD30 is restricted to subpopulations of activated T and B cells. CD30L is expressed primarily on activated T cells and subpopulations of B cells. The significance of CD30/CD30L interactions in immune regulation is not fully understood. Reported activities of CD30/CD30L in immune responses imply roles in regulation of secondary memory and antibody responses. Depending on the experimental system, both positive and negative regulation of immunoglobulin class switching and antibody production have been reported. Additionally, the biological activity of CD30/CD30L in animals has been difficult to assess due to the restricted and tightly regulated expression of this receptor-ligand pair. We generated transgenic mice with constitutive T cell specific overexpression of CD30L as a tool to help unravel the consequences of CD30/CD30L interactions in vivo. CD30L transgenic mice displayed a phenotype and responses to antigen challenge supporting a role for CD30/CD30L in promoting immunoglobulin class switching and antibody production. CD30L transgenic mice had increased numbers of germinal centers, elevated class-switched immunoglobulin isotypes, increased germinal center B cells and plasma cells, upregulation of genes indicative of B-cell activity, and exaggerated antibody responses to immune challenge. Interestingly, despite the heightened B-cell activity in CD30L transgenic mice, CD30L overexpression on T cells did not result in overt autoimmunity. Our results demonstrate that overexpression of CD30L on T cells promotes T cell-dependent B cell responses characterized by secondary antibody responses. Experiment Overall Design: Spleen, thymus, mesenteric lymph nodes and peripheral lymph nodes where samples from both CD30L transgenic and non-transgenic littermates (4 mice per group.)

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Integrated single cell multiomic profiling and functional validation reveal distinct cellular routes to human plasma cell differentiation.

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