Development of new genetic tools for selective targeting plasma cells

The National Institute of Allergy and Infectious Diseases awarded Duke University $161,500 under Project Grant R03AI195794 on April 1, 2026, to develop new genetic tools for selective targeting of plasma cells.

The recipient will develop new Cre and CreERT2 mouse models to enable gene targeting and tracing studies in plasma cells. Existing mouse models for plasma cell-selective genetic dissection have significant limitations due to leakiness into closely related cell lineages such as germinal center B cells and functionally intertwined cell lineages such as germinal center T cells. Duke identified a single gene displaying high-level expression in plasma cells but absent in other lymphoid lineages and will use it as a candidate for developing mouse models with improved selectivity and efficiency. The resulting models will support genetic and molecular investigations of plasma cell longevity and behavior in various tissues in response to infection or immunization.

Work will be performed in Durham, North Carolina. The performance period runs from April 1, 2026 through March 31, 2028. The award is made under the Allergy and Infectious Diseases Research program (CFDA 93.855), which supports biomedical research and research training in infectious diseases and related areas.

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.