ABSTRACT The duration of antibody-mediated immunity varies widely with the specific immunization or infection for reasons that remain difficult to understand or predict. The specific features of molecular circuitry in B cells and plasma cells that are responsible for these differences have still not been defined. In this application, which requests a second renewal of our R01 award, we seek to objectively define 1) molecular programs and cellular trajectories that lead to long-lived plasma cells in primary responses; 2) transcriptional and epigenetic features of memory B cells that precede durable recall responses. We will employ two BTB-POZ transcription factors that functionally oppose each other to gain molecular footholds on programs that control plasma cell lifespan. Modern single cell transcriptional and epigenetic programs will be employed alongside classic model antigens and adjuvants and new genetic tools to manipulate genes in vivo. Though the experimental plan is fundamental and basic in nature, the hope is that this work will lead to a set of rules that help predict and optimize the duration of humoral immunity.