Distinct expression of CD56 and CD19 marks molecular and functional endotypes of tetanus- versus RBD-specific human bone marrow plasma cells.

Plasma cell survival is influenced by various factors, including soluble mediators, intrinsic and extrinsic signals as well as adhesion molecules defining the bone marrow microenvironment. The role of their induction, turnover and competition dynamics among different antigen-specific bone marrow plasma cell subsets is not well understood. This study addresses the co-expression of CD19 and CD56 on both antigen-specific and total human bone marrow plasma cells (BMPC) using multiparametric flow cytometry and data from a previous single-cell RNA sequencing (scRNA-seq) study. While the RNA-seq data reflects characteristics of total BMPC, flow cytometry data enables detailed comparison of antigen-specific subsets, such as tetanus toxoid (TT)- and receptor binding domain (RBD, a region of the SARS-CoV-2 spike protein)-specific BMPC. CD56 expression is enriched among CD19- BMPC, particularly on those expressing IgG. RBD-specific BMPC typically lack CD56 expression, while TT-specific BMPC exhibit a substantially enriched CD56+CD19- BMPC population. Phenotypic and transcriptional characteristics (CD19 and NCAM1 [CD56] co-expression) together with distinct transcriptional profiles (including cell-cell adhesion, endopeptidase activity) and IgG/IgA expression identified remarkable differences between RBD-specific and TT-specific BMPC. These findings suggest that CD56 likely facilitates tissue retention of rather long-lived BMPC lacking CD19 expression. Given the emerging potential of selective BMPC subsets, this study may provide a rational for optimized vaccination protocols, as well as for selective plasma-cell targeting in autoimmunity. In this context, CD56+CD19- BMPC emerge as potential candidates for a long-lived and stable compartment.