Aims The adaptive immune response plays an important role in atherosclerosis. In response to a high-fat/high-cholesterol (HF/HC) diet, marginal zone B (MZB) cells activate an atheroprotective programme by regulating the differentiation and accumulation of ‘poorly differentiated’ T follicular helper (Tfh) cells. On the other hand, Tfh cells activate the germinal centre response, which promotes atherosclerosis through the production of class-switched high-affinity antibodies. We therefore investigated the direct role of Tfh cells and the role of IL18 in Tfh differentiation in atherosclerosis. Methods and results We generated atherosclerotic mouse models with selective genetic deletion of Tfh cells, MZB cells, or IL18 signalling in Tfh cells. Surprisingly, mice lacking Tfh cells had increased atherosclerosis. Lack of Tfh not only reduced class-switched IgG antibodies against oxidation-specific epitopes (OSEs) but also reduced atheroprotective natural IgM-type anti-phosphorylcholine (PC) antibodies, despite no alteration of natural B1 cells. Moreover, the absence of Tfh cells was associated with an accumulation of MZB cells with substantially reduced ability to secrete antibodies. In the same manner, MZB cell deficiency in Ldlr−/− mice was associated with a significant decrease in atheroprotective IgM antibodies, including natural anti-PC IgM antibodies. In humans, we found a positive correlation between circulating MZB-like cells and anti-OSE IgM antibodies. Finally, we identified an important role for IL18 signalling in HF/HC diet–induced Tfh. Conclusion Our findings reveal a previously unsuspected role of MZB cells in regulating atheroprotective ‘natural’ IgM antibody production in a Tfh-dependent manner, which could have important pathophysiological and therapeutic implications.

中文翻译：

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边缘区 B 细胞以 T 细胞依赖性方式产生“天然”动脉粥样硬化保护性 IgM 抗体

目的 适应性免疫反应在动脉粥样硬化中发挥重要作用。为了应对高脂肪/高胆固醇 (HF/HC) 饮食，边缘区 B (MZB) 细胞通过调节“低分化”滤泡辅助 T (Tfh) 细胞的分化和积累来激活动脉粥样硬化保护程序。另一方面，Tfh 细胞激活生发中心反应，通过产生类别转换的高亲和力抗体促进动脉粥样硬化。因此，我们研究了 Tfh 细胞的直接作用以及 IL18 在动脉粥样硬化中 Tfh 分化中的作用。方法和结果我们通过选择性基因删除 Tfh 细胞、MZB 细胞或 Tfh 细胞中的 IL18 信号传导，构建了动脉粥样硬化小鼠模型。令人惊讶的是，缺乏 Tfh 细胞的小鼠动脉粥样硬化加剧。缺乏 Tfh 不仅会减少针对氧化特异性表位 (OSE) 的类别转换 IgG 抗体，而且会减少动脉粥样硬化天然 IgM 型抗磷酸胆碱 (PC) 抗体，尽管天然 B1 细胞没有发生改变。此外，Tfh细胞的缺失与MZB细胞的积累相关，而MZB细胞分泌抗体的能力大大降低。以同样的方式，Ldlr−/− 小鼠中的 MZB 细胞缺陷与动脉粥样硬化 IgM 抗体（包括天然抗 PC IgM 抗体）的显着减少相关。在人类中，我们发现循环 MZB 样细胞与抗 OSE IgM 抗体之间呈正相关。最后，我们确定了 IL18 信号在 HF/HC 饮食诱导的 Tfh 中的重要作用。结论 我们的研究结果揭示了 MZB 细胞在以 Tfh 依赖性方式调节动脉粥样硬化保护性“天然”IgM 抗体产生中的先前未曾怀疑的作用，这可能具有重要的病理生理学和治疗意义。