Microenvironment regulates antibody secretion by IgA+ plasma cells.

Abstract

Abstract IgA secreting plasma cells (PCs) provide a critical supply of antibodies for barrier functions against pathogens. These cells express unique tissue-driven transcriptional profiles in their respective niches in the bone marrow (BM) and gut. We previously demonstrated that both tissues sustain long-lived IgA+ PCs, but the cell intrinsic and extrinsic signals responsible for survival and function in the gut remain largely unknown. Understanding how the microenvironment regulates tissue resident IgA+ PC functions has implications for maintaining intestinal homeostasis and protection from disease. We found that BM IgA+ PCs functionally differ from gut IgA+ PCs as they secrete significantly more antibody. To assess if this phenotype could be due to metabolic consequences, we profiled IgA+ PCs in both tissues. BM and gut IgA+ PCs have similar glucose and fatty acid uptake. However, BM IgA+ PCs have increased mitochondrial dependence, while gut IgA+ PCs have increased glycolytic capacity. We next altered the composition of the microbiome to determine the role of gut microbes in regulating tissue resident PCs. Our initial experiments used C57BL/6J mice with a well-defined low-complexity microbiome (from Jackson Labs). Co-housing Jax mice with animals containing a more diverse set of microbes led to an increase in antibody secretion. Herein, we identified that the tissue microenvironment and gut microbiome influences PC function. We aim to dissect the mechanisms involved in microbiome driven changes in PC phenotype. Ultimately, understanding how the microenvironment regulates intensity of PC antibody secretion provides a tool in targeting induction of systemic and mucosal responses and will improve vaccine design and development. Supported by grants from NIH (R35 GM147560, R03 AI156481)