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

摘要 胃肠道中的B淋巴细胞不断地受到共生微生物抗原的刺激。为了 防止共生生长和维持肠道内平衡，B细胞需要快速抗体反应 对抗细菌抗原。 为了完成这一任务，体液免疫系统依赖于一个复杂的多步骤B细胞增殖和 在生发中心的选择，最终产生抗体分泌浆细胞或记忆B细胞。 肠道B细胞在活化和分化过程中也暴露在饮食和微生物代谢产物中，但 这些环境信号如何影响B细胞在肠道中的命运和抗体反应目前还知之甚少。 因此，阐明本质上调节单个B细胞命运和功能的基本机制 肠道中的克隆仍然是免疫学的一个中心问题。 一些证据表明，代谢开关是生发中心B细胞反应的内在调节因子。 然而，B细胞如何将代谢物感觉与生发中心和抗体反应相结合仍未确定 约会。 在这个应用中，我们测试了这样的假设，即氧化形式的胆固醇25-HC直接控制 生发中心B细胞通过与固醇反应元件结合蛋白2(SREBP2)的相互作用而产生反应。 SREBP2是细胞内胆固醇稳态的关键调节因子，其在肠道中的转录活性 生发中心B细胞结合了肠道中的脂肪代谢和B细胞分化。我们还假设 滤泡树突状细胞(FDC)是一种位于生发中心的基质细胞，它能产生25-HC。 饮食中的胆固醇和微生物组，因此将快速变化的肠道内环境平衡与B细胞的命运联系起来。 越来越多的证据表明，25-HC控制着SREBP2的处理，但B中这种串扰的含义 到目前为止，还没有对肠道中的细胞进行研究。 我们的目标是：1)检验SREBP2活性控制生发中心B细胞转录谱和 B细胞命运；以及2)确定调节25-HC生态位的环境和细胞信号。 拟议中的研究考察了一种非常鲜为人知的串扰，即氧化形式的胆固醇、肠道 新陈代谢和适应性免疫系统激活。我们期望这些研究将增加我们的 了解肠道代谢如何塑造B细胞反应和适应性免疫。此外，这些研究 将为更好地理解脂肪代谢和分化之间的关系提供基础。 免疫细胞。

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.