Single cell clonal analysis identifies an AID‐dependent pathway of plasma cell differentiation

• Published in: EMBO reports 2022-12, Vol.23 (12), p.e55000-n/a
• Main Authors: Gómez‐Escolar, Carmen, Serrano‐Navarro, Alvaro, Benguria, Alberto, Dopazo, Ana, Sánchez‐Cabo, Fátima, Ramiro, Almudena R
• Format: Article
• Language: English
• Subjects: activation‐induced deaminase; Animals; Antibodies; Antigens; Cell activation; Cell Differentiation; Class switching; Differentiation (biology); EMBO11; EMBO13; EMBO19; Gene sequencing; germinal center; Germinal centers; Immunoglobulins; Immunological memory; Lymphocytes B; Memory cells; Mice; Pheochromocytoma cells; plasma cell; Plasma cells; Recombination; single cell sequencing; Somatic hypermutation; Transcriptomes
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202255000

Germinal centers (GC) are microstructures where B cells that have been activated by antigen can improve the affinity of their B cell receptors and differentiate into memory B cells (MBCs) or antibody‐secreting plasma cells. Here, we have addressed the role of activation‐induced deaminase (AID), which initiates somatic hypermutation and class switch recombination, in the terminal differentiation of GC B cells. By combining single cell transcriptome and immunoglobulin clonal analysis in a mouse model that traces AID‐experienced cells, we have identified a novel subset of late‐prePB cells (L‐prePB), which shares the strongest clonal relationships with plasmablasts (PBs). Mice lacking AID have various alterations in the size and expression profiles of transcriptional clusters. We find that AID deficiency leads to a reduced proportion of L‐prePB cells and severely impairs transitions between the L‐prePB and the PB subsets. Thus, AID shapes the differentiation fate of GC B cells by enabling PB generation from a prePB state. Synopsis A combination of single cell transcriptome and immunoglobulin gene sequencing identifies a novel pre‐plasmablast/plasma cell (L‐prePB) subset. Activation‐induced deaminase (AID) deficiency reduces this L‐prePB subset and the transition toward PB/PC cells. L‐prePB cells are non‐germinal center B cells with strong clonal relationships to PB/PC cells. AID deficiency compromises the generation and survival of L‐prePB cells. AID deficiency severely impairs transitions between L‐prePB and PB subsets. Graphical Abstract A combination of single cell transcriptome and immunoglobulin gene sequencing identifies a novel pre‐plasmablast/plasma cell (L‐prePB) subset. Activation‐induced deaminase (AID) deficiency reduces this L‐prePB subset and the transition toward PB/PC cells.