mTORC1 in B cells regulates antibody responses and promotes mitochondrial and metabolic fitness

Abstract B lymphocytes migrate among different micro-anatomic sites for diversification, selection, and eventual differentiation into antibody-secreting plasma cells. Emerging evidence supports the premise that aspects of the nutrient milieu vary within lymphoid micro-environments. However, the role of B cell-intrinsic metabolic programs in regulating B cell differentiation and antibody response quality remain unclear. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is essential for induction of Bcl6 and IRF4, key transcriptional regulators of germinal center and plasma cell fates. mTORC1 also enhances B cell proliferation upon exposure to antigen, increases the rate of somatic hyper-mutation, and is essential for generating high-affinity class switched antibodies. We also find that AMP-activated kinase (AMPK), an intracellular energy sensor, promotes plasma cell differentiation and antibody production. Collectively, these findings suggest mechanisms by which mTORC1 activity is critical for the germinal center reaction and producing class-switched, high-affinity antibodies, and indicate that AMPK can regulate the development and functional properties of terminally differentiated plasma cells. Supported by NIH R01 AI113292, HL106812, and NCI T32CA009592-29