Jchain-driven cre enables specific genetic manipulation and timestamping of plasma cell in their niche

Plasma cells produce antibodies that are essential for protection from infection and for vaccination success. Plasma cells are also at the origin of currently incurable hematological malignancies, most notably multiple myeloma. However, the study of gene function in plasma cells has mostly been performed using in vitro cultures and cell transfer systems that remove plasma cells from their microenvironment. Further, existing systems to genetically manipulate plasma cells are not specific and target multiple cell lineages including B cells, making it difficult to discriminate gene function in plasma cell formation and/or maintenance. Here we characterized a genetically engineered allele: Igjcre ERT2(GFP) that expresses GFP and cre ERT2 under the activity of the endogenous Jchain promoter. We found at the single cell level that Jchain expression occurred in plasma cells across immunoglobulin isotypes. Also using the Igjcre ERT2(GFP) we performed highly specific cre-loxP genetic manipulation of plasma cells residing in their natural microenvironment in vivo in the mouse and traced long-lived plasma cells. Highlights Jchain -driven cre-mediated genetic manipulation is effective only in plasma cells Jchain expression occurs in plasma cells across immunoglobulin isotypes Genetic manipulation using Jchain-driven cre targets plasma cells already in their niche Jchain- driven cre allows tracing of long-lived plasma cells Summary Plasma cells are essential for long-term protection from infection and underlie vaccination success. However, studies of gene function in plasma cells are hindered by technical limitations. Here we report an engineered allele that allows to trace and genetically manipulate plasma cells. Graphical Abstract