Abstract Secreted antibodies by plasma cells provide antigen specific humoral immunity, with long-lived plasma cells playing a critical role in immune memory responses. While recent studies have provided considerable insight into terminal differentiation of B cells into plasma cells, exactly how plasma cells are maintained long after antigen exposure remains enigmatic. Conditional gene targeting in animal models has permitted delineation of gene function and signaling networks in a cell type specific manner. Until now this technique could not be efficiently applied to plasma cells because of the lack of plasma cell specific Cre alleles. We propose to generate two strains which will allow genetic manipulation of this poorly understood lineage. Using state-of-the-art CRISPR/Cas9 gene editing approach we have knocked-in a codon optimized Cre into the IgJ locus that encodes the J chain polypeptide expressed selectively in all plasma cells. J chain polypeptide is necessary for multimerization of secreted IgM and IgA, but is expressed in all murine plasma cells. We will also generate a second Cre model, in which a codon optimized ligand inducible iCreERt2 will be knocked-into the same IgJ locus. Preliminary analysis of our first IgJ-iCre mice is highly promising, revealing plasma-cell specific expression of Cre recombinase. We will perform detailed analysis to further validate the cell specificity and efficiency of Cre activity by crossing the IgJ-iCre and IgJ-iCreERt2 mice to a reporter strain. The two plasma cell specific Cre alleles will, for the first time, provide the means to perform conditional gene targeting in this poorly understood lineage. Plasma cells play a central role in immune responses to pathogens and immunizations and are critical players in autoimmunity and cancer. These two plasma cell specific Cre lines have potential to facilitate a wide range of studies into signaling networks required for plasma cell differentiation, survival and function, multiple myeloma pathogenesis as well as genetic studies looking into the exact contribution of plasma cells to autoimmune and inflammatory diseases. The priority for our immunology lab, as outlined in Aim 2, is to investigate the role of B cell receptor (BCR) signaling and affinity of the BCR for antigen in the maintenance of long-lived plasma cells. We also intend to use the lineage tracing approach that will be made possible by the IgJ-iCreERt2 mice to characterize the differences between plasma cells that develop shortly after the immunogenic challenge and long-lived plasma cells that can be found in the bone marrow months after antigen exposure.