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: 10392434
• 负责人: Maria CECILIA BERIN
• 金额: $ 57.81万
• 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 2022-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392434
• 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.

摘要 免疫球蛋白介导的食物过敏是一种常见的疾病，在美国大约每13名儿童中就有1名受到影响。对许多人来说， 这是一种终生疾病，生活质量严重受损，没有FDA批准的治疗方法。虽然 免疫球蛋白E是食物过敏的病理生理学中心，对其维持知之甚少，是食物过敏的关键。 开发出真正能改变疾病的治疗方法。我们已经证明，维持小鼠的IgE需要 从CD4+T细胞产生IL-4，并阻断人类的IL-4/13信号表明，IgE需要 持续的Th2细胞因子的产生以维持。小鼠的免疫球蛋白记忆被控制在 抗原特异性的IgG+记忆细胞在T细胞的帮助下持续更新短暂的IgE+浆细胞池。 关于人类产生免疫球蛋白E的细胞基础缺乏相应的信息。我们假设 记忆中的免疫球蛋白G+B细胞是人类主要的B细胞亚群，过敏原特异性免疫球蛋白E就是从这些细胞亚群中衍生出来的 控制T细胞有帮助。我们发现在Th2细胞因子产生的CD4+T细胞中存在显著的异质性 食物过敏个体，包括常规Th2细胞、致病效应Th2细胞(PeTh2)和T滤泡 辅助类型2(Tfh2)细胞。我们认为，peTh2细胞在肠道组织中富含，在那里它们可以支持 类别-从过敏原特异性的免疫球蛋白记忆B细胞切换到IgE。我们认为Tfh2细胞富含 粘膜淋巴组织(扁桃体)支持从幼稚和记忆B细胞的类别切换，与 后者是高亲和力IgE的来源。此外，我们认为CD27+的常规Th2细胞是一种 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。在这项将T细胞和B细胞在食物过敏方面的专业知识结合在一起的多PI提案中， 我们将使用扁桃体、胃肠道活检和IgE患者的血液来验证这些陈述的假设。 介导性食物过敏。在免疫球蛋白E的背景下理解CD4+Th2亚群的维持和功能 介导性食物过敏将使我们能够设计治疗食物过敏的疾病修饰免疫疗法。