Dynamic nutrient sensing in plasma cells licenses immunoglobulin A secretion 2257718

Introduction Dietary cues modulate immunoglobulin A (IgA) production, thus impacting gut homeostasis and response to pathogens. However, molecular processes integrating nutrient sensing and translating it into specific downstream signaling for antibody secretion remain poorly understood. Methods To study the intrinsic pathways regulating IgA secretion, we isolated plasma cells from both mucosal and non-mucosal tissues, focusing on two metabolic pathways known to be upregulated in IgA-secreting plasma cells: the intracellular cholesterol sensor Sterol Regulatory Element-Binding Protein 2 (SREBP2) and the mammalian target of rapamycin complex 1 (mTORC1). We then used in vitro-differentiated plasma cells to test whether depleting SREBP2–either genetically or pharmacologically–affects IgA secretion, using the ELISPOT assay for measurement. Finally, we employ conditional knockout mice lacking SREBP2 and mTORC1 specifically in plasma cells to study their function in antibody secretion in vivo. Results Here, we identified that both SREBP2 and mTORC1 work synergistically as metabolic checkpoints controlling IgA plasma cell secretion. SREBP2 regulates B lymphocyte-induced maturation protein-1 (Blimp-1) in response to cholesterol metabolites, while mTORC1 amplifies SREBP2 activation through direct phosphorylation. Screening for mTORC1 agonists revealed alanine as the dominant amino acid enhancing IgA, but not IgG, secretion, an effect independent of anatomical location and conserved in human plasma cells. Finally, alanine supplementation enhances protective, antigen-specific IgA to oral immunization and infection. Conclusion Our work elucidates metabolic processes required for integrating nutrients in plasma cells and has implications for developing therapeutics that modulate IgA production.