Development of new genetic tools for selective targeting plasma cells

About This Grant

Abstract Plasma cell (PCs) antibody production is at the core of humoral immunity and inherently critical to the success of almost all existing vaccines. Their ability to persist and secret antibodies long after pathogen exposure or immunization provides long term sometimes lifelong immune protection against future encounter of the pathogens. What are the molecular pathways dictating the lifespan of PCs during their generation and subsequent maintenance remain largely unknown. Equally unknown are the regulators that control the diversity and activity of PCs reside in various lymphoid and non-lymphoid tissues. Cell lineage specific gene targeting and tracing (GT&T) with the Cre/LoxP system has been proven vital to understand the biology and regulation of various types of cells, especially rare cell populations such as PCs. However, existing mouse models for PC selective GT&T have significant drawbacks due to leakiness in either closely related cell lineage such as germinal center B cells or functionally intertwined cell lineage such as germinal center T cells. To improve selectivity in genetic dissection of PCs, we searched for genes that display high level expression in PCs but absent in the rest of lymphoid lineages. We found a single gene that fulfills this criterion and thus a good candidate for developing new mouse models with high selectivity and efficiency to drive Cre/CreERT2 expression in PCs. We propose to develop new Cre and CreERT2 models for GT&T studies in PCs. The proposed mouse model will address the immediate need for genetic and molecular investigations aimed at understanding longevity and behaviors of PCs in various tissues in response to infection or immunization.