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，并花费数十亿美元 每年的医疗保健和生产力损失。IgE是速发型超敏反应的主要介质 过敏反应的阶段，也可以驱动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，并需要IL-4分泌性T滤泡辅助细胞（TFH）的帮助 细胞TFH细胞定位于GC，在那里它们促进B细胞克隆扩增和抗体亲和力 成熟一个主要的未解决的问题是什么因素控制TFH细胞的发展，促进IgE 应答高亲和力IgE抗体在过敏反应中形成，所述过敏反应涉及IL-4的产生。 表达TH 2细胞和表达IL-4的TFH细胞（有时称为TFH 2细胞）。但 在过敏反应中产生的TH 2细胞和TFH 2细胞之间的发育联系尚不清楚。 此外，表达IL-4的TFH细胞可以在不产生显著IgE应答的情况下发育。 在最近的一项研究中，使用小鼠食物过敏引发模型，我们表征了TFH细胞， 使用相同的变应原和佐剂，在两种不同的引发方法下开发，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， 基因表达的显著差异。在两种引发条件下，表达IL-4的TFH细胞发育，但 IgE反应仅在一种引发条件下发生。我们称这种促进IgE的TFH细胞为 系统作为TFH-IgE细胞，以将它们与TFH 2细胞区分开。 我们在本申请中的目标是定义TFH-IgE细胞开发的要求。我们发现 Anxa 1是一种已知的TH 2和IgE反应抑制剂， TFH-IgE细胞与TFH 2细胞相比。Anxa 1在TFH细胞功能中的作用以前没有被发现。 然而，新的研究结果表明，Anxa 1的表达是下调的IL-4信号在活化的细胞， CD 4 T细胞。因此，我们假设Anxa 1是一种信号调节蛋白，它抑制了 并且与TFH 2细胞相反，TFH-IgE细胞由IL-4-Stat 6信号产生， 临界下调Anxa 1表达以允许完全TFH-IgE分化（特征在于IL-4增加， CD 40 L; Fgl 2和Entpd 1降低）。