Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
Cell Rep. 2022 Jun 28;39(13):110990. doi: 10.1016/j.celrep.2022.110990.
Immunoglobulin E (IgE) responses are a central feature of allergic disease. Using a well-established food-allergy model in mice, we show that two sensitizations with cognate B cell antigen (Ag) and adjuvant 7 days apart promotes optimal development of IgE+ germinal center (GC) B cells and high-affinity IgE production. Intervals of 3 or 14 days between Ag sensitizations lead to loss of IgE+ GC B cells and an undetectable IgE response. The immunosuppressive factors Fgl2 and CD39 are down-regulated in T follicular helper (TFH) cells under optimal IgE-sensitization conditions. Deletion of Fgl2 in TFH and T follicular regulatory (TFR) cells, but not from TFR cells alone, increase Ag-specific IgE levels and IgE-mediated anaphylactic responses. Overall, we find that Ag-specific IgE responses require precisely timed stimulation of IgE+ GC B cells by Ag. Furthermore, we show that Fgl2 is expressed by TFH cells and represses IgE. This work has implications for the development and treatment of food allergies.
免疫球蛋白 E（IgE）反应是过敏疾病的一个主要特征。我们使用一种成熟的小鼠食物过敏模型表明，两次同源 B 细胞抗原（Ag）和佐剂致敏，间隔 7 天，可促进 IgE+生发中心（GC）B 细胞的最佳发育和高亲和力 IgE 的产生。Ag 致敏间隔 3 天或 14 天，会导致 IgE+GC B 细胞丢失和无法检测到 IgE 反应。在最佳 IgE 致敏条件下，免疫抑制因子 Fgl2 和 CD39 在滤泡辅助性 T 细胞（TFH）细胞中下调。TFH 和 T 滤泡调节性（TFR）细胞而非 TFR 细胞中 Fgl2 的缺失会增加抗原特异性 IgE 水平和 IgE 介导的过敏反应。总的来说，我们发现 Ag 特异性 IgE 反应需要 Ag 精确地刺激 IgE+GC B 细胞。此外，我们表明 Fgl2 由 TFH 细胞表达并抑制 IgE。这项工作对食物过敏的发展和治疗具有重要意义。
