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

项目摘要 在全世界高达40%的人口中检测到环境蛋白的IgE抗体， 过敏性疾病的流行在工业化国家持续上升。虽然有几种疗法可以减轻 抗体驱动的过敏反应或阻断抗体效应子功能，高死亡率持续存在，没有治愈 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。 我们小组和其他人以前的工作表明，胸腺基质细胞生成素（TSLP）是胸腺发育所必需的。 发展过敏性疾病，我们最近发现TSLP也发挥了额外的作用，在控制 老年中心（GC）的IgE和IgG 1抗体产生。GC B细胞和T滤泡辅助细胞上调 表面TSLP受体（TSLPR）的表达，因为它们进入GC微环境，和TSLPR- 缺陷型小鼠在免疫后产生显著较低滴度的抗原特异性IgG 1和IgE。当CD 4 + T细胞特异性缺乏TSLPR表达（CD 4creTSLPRF/F），免疫小鼠产生类似频率的TSLPR表达。 抗原特异性生发中心，但对抗原具有高亲和力的产生IgG 1的B细胞数量较少， 提示T细胞上的TSLPR表达可能是生发中心亲和力成熟所需的。 因此，我们假设Tfh细胞和生发中心B细胞对生发中心活性的调节存在差异 两种不同的机制。在这里，我们将询问TSLPR信号在这些细胞群中的每一个中是如何传递的。 在小鼠模型中独立调节IgE/IgG 1抗体的产生，我们将进行随访 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， 猫过敏患者体内的转铁蛋白细胞。总的来说，我们对TSLP受体信号传导之间联系的研究 和过敏原特异性生发中心反应可以建立一个基础，建立新的疗法来治疗 或预防过敏性疾病的发生。

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.