Regulation of germinal centers by thymic stromal lymphopoietin in mice and humans

项目总结 在全世界高达40%的人口中检测到针对环境蛋白的免疫球蛋白E抗体， 在工业化国家，过敏性疾病的流行率继续上升。尽管有几种疗法可以缓解 抗体驱动的过敏反应或阻断抗体效应器的功能，高死亡率持续不治本 治疗，以及控制过敏原特异性抗体产生的机制仍然知之甚少。 我们小组和其他人之前的工作表明，胸腺间质淋巴生成素(TSLP)是 发展为过敏性疾病，我们最近发现TSLP在控制 生发中心(GCs)产生IgE和IgG1抗体。GC B细胞和T滤泡辅助细胞上调 表面TSLP受体(TSLPR)进入GC微环境后的表达，以及TSLPR- 缺陷小鼠在免疫后产生明显较低的抗原特异性IgG1和IgE滴度。当CD4+ T细胞特异性缺乏TSLPR表达(CD4creTSLPRF/F)，免疫小鼠出现类似的频率 抗原特异性生发中心，但对抗原具有高亲和力的产生IgG1的B细胞数量较少， 提示T细胞表达TSLPR可能是生发中心亲和力成熟所必需的。 因此，我们假设Tfh细胞和生发中心B细胞对生发中心的活动有不同的调节作用。 通过两种不同的机制。在这里，我们将询问TSLPR信号在这些细胞群体中是如何 独立调节小鼠模型中IgE/IgG1抗体的产生，我们将进行后续研究 实验证实，TLSP阻断疗法可以减少过敏原特异性浆细胞的数量，并 猫过敏患者的TFH细胞。总体而言，我们对TSLP受体信号之间的联系的研究 而过敏原特异性生发中心的反应可能为建立新的治疗方法奠定基础 或预防过敏性疾病的发作。

PROJECT SUMMARY IgE antibodies to environmental proteins are detected in up to 40% of the worldwide population, and the prevalence of allergic disease continues to rise in industrialized nations. Although several therapies can mitigate antibody-driven anaphylaxis or block antibody effector functions, high mortality rates persist without a curative treatment, and the mechanisms that control allergen-specific antibody production are still poorly understood. Previous work from our group and others showed that Thymic Stromal Lymphopoietin (TSLP) is required for the development allergic disease, and we recently discovered that TSLP also plays an additional role in controlling IgE and IgG1 antibody production in germinal centers (GCs). GC B cells and T follicular helper cells upregulate the expression of surface TSLP receptor (TSLPR) as they enter into the GC microenvironment, and TSLPR- deficient mice produce significantly lower titers of antigen-specific IgG1 and IgE upon immunization. When CD4+ T cells specifically lack TSLPR expression (CD4creTSLPRF/F), immunized mice develop similar frequencies of antigen-specific germinal centers, but lower numbers of IgG1-producing B cells with high-affinity for antigen, suggesting that TSLPR expression on T cells may be required for affinity maturation in the germinal center. Therefore, we hypothesize that Tfh cells and germinal center B cells differentially regulate germinal center activity by two distinct mechanisms. Here, we will ask how TSLPR signaling in each of these cell populations independently regulate the production of IgE/IgG1 antibodies in mouse models, and we will perform follow-up experiments to confirm that TLSP-blocking therapy can reduce the number of allergen-specific plasma cells and Tfh cells in patients with cat allergies. Overall, our research into the connection between TSLP receptor signaling and allergen-specific germinal center responses could build a foundation to establish novel therapeutics to treat or prevent the onset of allergic disease.