Heterogeneity of T cell phenotype and function in food allergy

食物过敏中 T 细胞表型和功能的异质性

• 批准号: 10165496
• 负责人: Maria CECILIA BERIN
• 金额: $ 83.47万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10165496
• 关键词: Address; Affect; Affinity; Allergen Immunotherapy; Allergens; Allergic; Allergy to eggs; Allergy to peanuts; Antibodies; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; BLR1 gene; Biopsy; Blood; Blood Circulation; CD4 Positive T Lymphocytes; Cell Compartmentation; Cell Maintenance; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Child; Cues; Disease; Duodenum; FDA approved; Flow Cytometry; Food; Food Hypersensitivity; Functional disorder; Generations; Half-Life; Heterogeneity; Human; IL4 gene; IL5 gene; IL9 gene; IgE; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunotherapy; Impairment; In Vitro; Individual; Interleukin-13; Interleukin-4; Intervention; Intestines; Location; Lymphoid Tissue; Maintenance; Mediating; Memory; Memory B-Lymphocyte; Mucous Membrane; Mus; Oral; Outcome; Outcomes Research; Pathogenicity; Patients; Phenotype; Plasma Cells; Population; Production; Quality of life; Regulation; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Site; Source; Specimen; Supporting Cell; System; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF5 gene; Testing; Th2 Cells; Time; Tissues; Tonsil; Up-Regulation; Work; cytokine; design; effector T cell; food allergen; food challenge; gastrointestinal; high dimensionality; interleukin-13 receptor; lymph nodes; neutralizing antibody; omalizumab; pathogen; peripheral blood; response; single-cell RNA sequencing; therapeutic target

SUMMARY IgE-mediated food allergy is a common disease affecting approximately 1 in 13 children in the USA. For many, this is a lifelong disease with significant impairment in quality of life and no FDA-approved treatment. Although IgE is central to the pathophysiology of food allergy, the maintenance of IgE is poorly understood and is key to developing treatments that are truly disease modifying. We have shown that maintenance of IgE in mice requires IL-4 production from CD4+ T cells, and blocking IL-4/13 signaling in humans demonstrates that IgE requires continual Th2 cytokine production for maintenance. IgE memory in mice is contained within a population of antigen-specific IgG+ memory cells that continually renew the short-lived IgE+ plasma cell pool with T cell help. There is a lack of corresponding information on the cellular basis of IgE production in humans. We hypothesize that memory IgG+ B cells are the main B cell subset in humans from which allergen-specific IgE is derived under control of T cell help. We have identified significant heterogeneity in Th2 cytokine producing CD4+ T cells from food allergic individuals, including conventional Th2 cells, pathogenic effector Th2 cells (peTh2), and T follicular helper type-2 (Tfh2) cells. We propose that peTh2 cells are enriched in intestinal tissues where they can support class-switch to IgE from allergen-specific IgG memory B cells. We propose that Tfh2 cells are enriched in mucosal lymphoid tissues (tonsils) where they support class switch from naïve and memory B cells, with the latter being the source of high-affinity IgE. Furthermore, we propose that CD27+ conventional Th2 cells are a reservoir of memory that maintain the pool of Tfh2 and peTh2 cells through local cues in the lymphoid tissues and mucosa, respectively. In this multi-PI proposal bringing together T cell and B cell expertise in food allergy, we will test these stated hypotheses using tonsil, gastrointestinal biopsies, and blood from patients with IgE- mediated food allergy. Understanding the maintenance and function of CD4+ Th2 subsets in the context of IgE- mediated food allergy will allow us to design disease modifying immunotherapies for the treatment of food allergy.

概括 IgE介导的食物过敏是一种常见的疾病，影响了美国13名儿童中约1个。对于许多人 这是一种终生疾病，其生活质量有重大损害，没有FDA批准的治疗。虽然 IgE对于食物过敏的病理生理学是核心 开发真正正在修改的治疗方法。我们已经表明，小鼠的IgE维护需要 从CD4+ T细胞产生IL-4，并阻止人类的IL-4/13信号传导表明IgE需要 连续Th2细胞因子生产进行维护。小鼠的IgE记忆包含在 抗原特异性的IgG+记忆细胞不断使用T细胞帮助不断更新短暂的IgE+等离子体细胞池。 关于人类IgE产生的细胞基础，缺乏对应信息。我们假设 记忆IgG+ B细胞是人类的主要B细胞子集 控制T细胞帮助。我们已经确定了来自Th2细胞因子的显着异质性，从而产生了CD4+ T细胞 食物过敏个体，包括常规TH2细胞，致病效应Th2细胞（Peth2）和T卵泡 助手类型2（TFH2）细胞。我们建议将Peth2细胞富集在可以支撑的肠里 从过敏原特异性IgG记忆B细胞中向IgE进行类转换。我们建议将TFH2细胞富集在 粘膜淋巴组织（扁桃体），它们支持阶级从幼稚和记忆B细胞转变为 后者是高亲和力IgE的来源。此外，我们建议CD27+常规TH2细胞是一个 通过淋巴组织中的局部线索维持TFH2和Peth2细胞池的记忆库 和粘膜分别。在此多PI提案中 我们将使用扁桃体，胃肠道活检和IgE-患者的血液检验这些既定假设 介导的食物过敏。了解在IgE的背景下CD4+ TH2子集的维护和功能 介导的食物过敏将使我们能够设计用于治疗食物过敏的免疫疗法的疾病。