Diet-derived oxysterols shape intestinal B cell fate by controlling intracellular cholesterol metabolism

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Abstract B lymphocytes in the gastrointestinal tract are constantly stimulated by commensals microbial antigens. In order to prevent commensal outgrowth and maintain intestinal homeostasis, B cells need to mount a rapid antibody response against bacterial antigens. To achieve this task, the humoral immune system relies on a complex multistep process of B cell proliferation and selection in the germinal center, which eventually gives rise to either antibody secreting plasma cells or memory B cells. Intestinal B cells are also exposed to dietary and microbial metabolites during their activation and differentiation, but how these environmental cues shape B cell fate and antibody response in the gut is poorly understood. Therefore, elucidating the fundamental mechanisms that intrinsically regulate the fate and function of individual B cell clones in the gut remains a central question in immunology. Several lines of evidence indicate that metabolic switches act as intrinsic regulators of germinal center B cell response. However, how B cells integrate metabolite sensing with germinal center and antibody response remains undefined to date. In this application we test the hypothesis that the oxysterol 25-HC, an oxidized form of cholesterol, directly controls germinal center B cell response through its interaction with the Sterol Response Element Binding Protein 2 (SREBP2). SREBP2 is a key regulator of intracellular cholesterol homeostasis, and its transcriptional activity in the intestinal germinal center B cells couples lipid metabolism and B cell differentiation in the intestine. We also hypothesize that follicular dendritic cells (FDCs), stromal cells which are located in the germinal center, produce 25-HC in response to dietary cholesterol and microbiome, therefore linking rapidly changing intestinal homeostasis to B cell fate. Accumulating evidence indicates that 25-HC controls SREBP2 processing, but the implication for this cross talk in B cells in the gut has not been investigated so far. Our aims are: 1) To test the hypothesis that SREBP2 activity controls germinal center B cell transcriptional profile and B cell fate; and 2) To define the environmental and cellular cues that regulate 25-HC niche. The proposed studies examine a very poorly understood crosstalk between oxidized form of cholesterol, intestinal metabolism and adaptive immune system activation. It is our expectation that these studies will increase our understanding of how intestinal metabolism shapes B cell responses and adaptive immunity. Furthermore, these studies will provide a foundation for better understanding of the relationship between lipid metabolism and differentiation in immune cells.