Plasma cell mitochondrial pyruvate import controls the duration of humoral immunity.

Abstract

Abstract Durable antibody production after vaccination or infection is mediated by long-lived plasma cells. Pathways that specifically allow long-lived plasma cells to persist remain unknown. Through bioenergetic profiling, we demonstrate that human and mouse long-lived plasma cells possess much greater mitochondrial spare respiratory capacity than do short-lived plasma cells. Inhibition of mitochondrial pyruvate import in long-lived plasma cells attenuates spare, but not basal respiration. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, leads to a progressive loss of long-lived plasma cells and vaccine-specific antibodies in vivo. Long-lived plasma cells uptake more glucose than do their short-lived counterparts, and subsequent catabolism to pyruvate is essential for spare respiratory capacity. IL-4 or IFNg treatment of activated B lymphocyte precursors to plasma cells promotes glucose uptake. Thus, signals provided to precursors, glucose uptake, and mitochondrial pyruvate transport allow long-lived plasma cells to provide enduring antibody-mediated immunity.