Metabolic Regulation of Plasma Cell Function

IgA+ plasma cells (PCs) provide robust humoral immunity against pathogenic and commensal bacteria. These cells supply critical antibodies for barrier function at mucosal surfaces. IgA+ PCs are found in large numbers in the gut lamina propria and systemic sites such as the bone marrow (BM). In this thesis, we found that IgA+ PCs in the gut secrete significantly fewer antibodies compared to IgA+ PCs in BM. While the cell-intrinsic and -extrinsic signals responsible for regulating BM PC function have been extensively studied, the regulatory signals in the gut remain largely unknown. Understanding how antibody secretion is regulated in tissue-resident PCs can be leveraged to optimize better antibody responses. Recent findings have determined that the metabolic environment in the BM niche determines efficiency of antibody secretion. Thus, we sought to determine if decreased gut IgA+ PC antibody secretion could be due to differential metabolism. Utilizing a single cell flow cytometry-based metabolism assay (SCENITH), we found that gut IgA+ PCs have an increased glycolytic capacity, compared to increased mitochondrial dependence in BM IgA+ PCs. Gut IgA+ PCs have cellular phenotype consistent with a cell undergoing glycolysis. Furthermore, when key bioenergetic pathways were inhibited both ex vivo and in vivo, we found that glycolytic activity regulates antibody secretion in the gut. We hypothesized that nutrient availability could be a determining extrinsic governor of regulating PC metabolism and subsequent antibody secretion in the gut. Therefore, we introduced a high fat, no carbohydrate ketogenic diet that promotes fatty acid oxidation metabolism and limits glycolytic activity. We saw a significant increase in antibody secretion in gut IgA+ PCs. Exploring microbiome and nutrient effects on this diet induced antibody secretion in the gut led us to determine that ketogenic diet induced a metabolic phenotype in gut IgA+ PCs consistent with oxidative phosphorylation. Herein, we observed that metabolism regulates PC function in the gut. We aim to further investigate the direct and indirect contributing factors that determine the gut IgA+ plasma cell glycolytic program. Ultimately, understanding extrinsic and intrinsic regulators of antibody secretion in the gut will provide tools for sustaining intestinal homeostasis and targeting mucosal pathogen responses.

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Metabolic Regulation of Plasma Cell Function

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