Durable antibody immunity depends on long-lived plasma cells (LLPCs) that primarily reside in the bone marrow (BM). However, due to LLPC rarity, it has not been possible to defne their phenotypes or determine their heterogeneity. By single-cell mRNA sequencing, cytometry and a genetic pulse–chase mouse model, we show that IgG and IgM LLPCs display an EpCAMhiCXCR3–phenotype, whereas IgA LLPCs are Ly6AhiTigit–. While IgG and IgA LLPCs are mainly contributed by somatically hypermutated cells following immunization or infection, cells with innate properties and public antibodies are found in IgA and IgM LLPC compartments. Particularly, IgM LLPCs are highly enriched with public clones shared among diferent individual animals, diferentiated in a T cell-independent manner and have afnity for self-antigens and microbial-derived antigens. Taken together, our work reveals diferent routes toward LLPC development and paves the way for deeper understanding of cellular and molecular underpinnings of long-term antibody immunity.
