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的生活质量，耗资数十亿美元 每年进行医疗保健和生产力降低。 IgE是立即高敏性的主要中介者 过敏反应的阶段，也可以驱动威胁生命的过敏反应。过敏原特异性IgE是 在生发中心（GC）反应中产生，需要通过分泌T卵泡助手（TFH）来帮助 细胞。 TFH细胞位于GC，它们促进B细胞克隆膨胀和抗体亲和力 成熟。一个未解决的主要问题是哪些因素控制着促进IgE的TFH细胞的发展 回答。高亲和力IgE抗体是在涉及IL-4-发展的过敏反应中形成的 表达Th2细胞和表达IL-4的TFH细胞（有时称为TFH2细胞）。但是， 在过敏反应和TFH2细胞中产生的Th2细胞之间的发展连接尚未解决。 另外，表达IL-4的TFH细胞可以发育，而无需产生重要的IgE响应。 在最近的一项研究中，使用小鼠中的食物过敏启动模型，我们表征了TFH细胞 使用相同的过敏原和辅助剂的两种不同的启动方法开发，但在 启动的时间。我们分析了在这两个条件下开发并确定的TFH细胞 基因表达的显着差异。在这两种启动条件下，表达IL-4的TFH细胞都会发展出来，但 IgE响应仅在一个启动条件下发展。我们称为促进IgE的TFH细胞 系统作为TFH-IGE细胞，将它们与TFH2细胞区分开。 我们在此应用程序中的目标是定义对TFH-IGE细胞开发的要求。我们找到了 Anxa1是一种已知的Th2和IgE反应抑制剂的调节基因，被强烈下调 与TFH2细胞相比，在TFH-IGE细胞中。 Anxa1在TFH细胞功能中的作用以前尚未 经过探索，但是新发现表明，激活的IL-4信号传导下调了Anxa1的表达 CD4 T细胞。因此，我们假设Anxa1是一种抑制发育的信号调节蛋白 TFH-IgE细胞，与TFH2细胞相反，TFH-IgE细胞是由IL-4-STAT6信号产生的 严重下调Anxa1的表达以允许完全TFH-IgE分化（以IL-4的增加为特征 CD40L;减少FGL2和ENTPD1）。