The usage of metabolic pathways is tailored to meet the specific functions and demands of a given cell type. Of particular interest is how metabolism supports the survival and antibody secretion of long-lived cells, the primary cell type that is responsible for humoral immunity. Using plasma cells as a model system, we will define how glucose and amino acid uptake supports long-term persistence of these antibody-secreting cells. In preliminary data, we demonstrate that long-lived plasma cells import far more glucose than do their short-lived counterparts. Glucose is primarily used to glycosylate antibodies, but a portion of this glucose can be used for glycolysis, and the resultant pyruvate imported into the mitochondria. Short-lived plasma cells do not have this capacity. We propose to define the metabolic fates of pyruvate and explain why this pathway is important in long-lived plasma cells. We also propose to define how long-lived plasma cells balance enhanced antibody production with nutrient uptake and ER stress. Finally, we seek to define the physiological signals that promote plasma cell metabolic programs following vaccination. The application heavily emphasizes new genetic and in vivo approaches to define, report, and functionally test critical metabolic pathways in a cell type critical for humoral immunity.
The length of time that antibodies persist after vaccination and infection and the efficacy of these antibodies against related pathogens varies widely. The goal of this proposal is to identify metabolic pathways that control the duration of immunity after vaccination.
|Lam, Wing Y; Jash, Arijita; Yao, Cong-Hui et al. (2018) Metabolic and Transcriptional Modules Independently Diversify Plasma Cell Lifespan and Function. Cell Rep 24:2479-2492.e6|
|Egawa, Takeshi; Bhattacharya, Deepta (2018) Regulation of metabolic supply and demand during B cell activation and subsequent differentiation. Curr Opin Immunol 57:8-14|