TFH cell programming for IgE responses

TFH 细胞编程以实现 IgE 反应

• 批准号: 10682057
• 负责人: Alexander L Dent
• 金额: $ 23.01万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682057
• 关键词: Adjuvant; Affinity; Allergens; Allergic; Allergic Disease; Anaphylaxis; Antibodies; Antibody Affinity; Antigens; Asthma; B-Lymphocytes; Bone Marrow; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chimera organism; Clonal Expansion; Data; Development; Food Hypersensitivity; Gene Expression; Glucocorticoids; Goals; Healthcare; Helper-Inducer T-Lymphocyte; IL4 gene; IgE; Immediate hypersensitivity; Immune response; Interleukin-2; Interleukin-4; Knockout Mice; Life; Light; Literature; Mediator; Methods; Modeling; Mus; Pathway interactions; Phase; Production; Productivity; Proteins; Quality of life; Reaction; Regulation; Regulator Genes; Role; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; System; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF5 gene; Testing; Th2 Cells; United States; Work; allergic airway inflammation; allergic response; cost; human disease; inhibitor; insight; novel; novel therapeutics; response; targeted treatment

Allergic disease greatly impacts the quality of life in the United States and costs billions of dollars annually on health care and lost productivity. IgE is the primary mediator for the immediate hypersensitivity phase of the allergic response and can also drive life-threatening anaphylaxis. Allergen-specific IgE is produced in germinal center (GC) reactions and requires help from IL-4-secreting T follicular helper (TFH) cells. TFH cells localize to the GC, where they promote B cell clonal expansion and antibody affinity maturation. A major unresolved question is what factors control the development of TFH cells that promote IgE responses. High affinity IgE antibodies are formed in allergic responses which involve the development of IL-4- expressing TH2 cells and IL-4-expressing TFH cells (sometimes referred to as TFH2 cells). However, the developmental connection between TH2 cells generated in allergic responses and TFH2 cells is unresolved. Additionally, IL-4-expressing TFH cells can develop without the production of significant IgE responses. In a recent study, using a food allergy priming model in mice, we characterized TFH cells that developed under two different methods of priming using the same allergen and adjuvant, but varying in the timing of the priming. We analyzed the TFH cells that developed under these two conditions and identified significant differences in gene expression. In both priming conditions, IL-4-expressing TFH cells developed, but IgE responses only developed in only one priming condition. We termed the TFH cells that promote IgE in this system as TFH-IgE cells, to distinguish them from TFH2 cells. Our goal in this application is to define the requirements for TFH-IgE cell development. We have found that Anxa1, a regulatory gene which is a known inhibitor of TH2 and IgE responses, is strongly down-regulated in TFH-IgE cells compared to TFH2 cells. The role of Anxa1 in TFH cell function has not been previously explored, however new findings reveal that Anxa1 expression is down-regulated by IL-4 signaling in activated CD4 T cells. We therefore hypothesize that Anxa1 is a signal modulating protein that inhibits the development of TFH-IgE cells, and that, in contrast to TFH2 cells, TFH-IgE cells are generated by IL-4-Stat6 signals which critically down-regulate Anxa1 expression to allow full TFH-IgE differentiation (characterized by increased IL-4, CD40L; decreased Fgl2 and Entpd1).

过敏性疾病极大地影响了美国人的生活质量并造成数十亿美元的损失 每年都会因医疗保健和生产力损失而遭受损失。 IgE 是速发型超敏反应的主要介质 过敏反应的阶段，也可能导致危及生命的过敏反应。过敏原特异性 IgE 是 在生发中心 (GC) 反应中产生，需要分泌 IL-4 的滤泡辅助 T (TFH) 的帮助 细胞。 TFH 细胞定位于 GC，促进 B 细胞克隆扩增和抗体亲和力 成熟。一个尚未解决的主要问题是哪些因素控制促进 IgE 的 TFH 细胞的发育 回应。高亲和力 IgE 抗体是在过敏反应中形成的，涉及 IL-4- 的产生 表达TH2细胞和表达IL-4的TFH细胞（有时称为TFH2细胞）。然而， 过敏反应中产生的 TH2 细胞和 TFH2 细胞之间的发育联系尚未解决。 此外，表达 IL-4 的 TFH 细胞可以在不产生显着 IgE 反应的情况下发育。 在最近的一项研究中，我们利用小鼠食物过敏启动模型，对 TFH 细胞进行了表征 使用相同的过敏原和佐剂，通过两种不同的引发方法开发，但在 启动的时间。我们分析了在这两种条件下发育的 TFH 细胞并确定 基因表达的显着差异。在两种启动条件下，表达 IL-4 的 TFH 细胞均得以发育，但 IgE 反应仅在一种启动条件下产生。我们将促进 IgE 的 TFH 细胞称为 系统作为 TFH-IgE 细胞，以将其与 TFH2 细胞区分开。 我们在此应用中的目标是定义 TFH-IgE 细胞开发的要求。我们发现 Anxa1 是一种调节基因，已知是 TH2 和 IgE 反应的抑制剂，被强烈下调 与 TFH2 细胞相比，在 TFH-IgE 细胞中。 Anxa1 在 TFH 细胞功能中的作用此前尚未被报道 然而，新的研究结果表明，Anxa1 的表达在激活的细胞中被 IL-4 信号下调。 CD4 T 细胞。因此，我们假设 Anxa1 是一种信号调节蛋白，可抑制发育 TFH-IgE 细胞，与 TFH2 细胞相比，TFH-IgE 细胞是由 IL-4-Stat6 信号产生的， 严重下调 Anxa1 表达以实现 TFH-IgE 完全分化（其特征是 IL-4、 CD40L；减少 Fgl2 和 Entpd1)。