CD28 signaling in long lived plasma cells regulates glycolysis for survival and antibody production. (P1469)

Abstract

Abstract Recent evidence suggests that sustained humoral immunity is dependent upon bone marrow resident long-lived antibody secreting plasma cells (LLPCs). However, the signaling pathways that define LLPC survival and function are not completely understood. We have shown that CD28 signaling in LLPCs is necessary for their survival and sustained antibody production. In T cells, CD28 is known to regulate the induction of glycolysis during activation. What is unclear is how CD28 may regulate metabolism in plasma cells. It is also recognized that many of the molecular pathways governing LLPC cell survival are also observed in multiple myeloma, the transformed counterpart of plasma cells. Here we demonstrate that CD28-mediated signaling induces glut1 expression and that poisoning glycolysis inhibits proliferation and antibody production in both plasma cells and multiple myeloma cells. Interestingly, inhibition of glycolysis inactivates AMPK, a major metabolic sensor responsible for facilitating fatty acid oxidation (FAO). Furthermore, induction of AMPK by AICAR could not rescue the defects induced by glycolytic inhibition, suggesting that LLPCs require CD28-mediated glycolytic end products for both biosynthesis and oxidative energy production. By understanding the metabolic regulation of plasma cell induction, maintenance, and function, we may find insight into how targeting metabolism may alter both long-term humoral immunity and how we can use this knowledge to treat multiple myeloma.