Control of IL-4 by gamma/delta T Cells

γ/δ T 细胞对 IL-4 的控制

• 批准号: 9181325
• 负责人: WILLI K BORN
• 金额: $ 24.24万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181325
• 关键词: Adult; Affect; Allergic; Antibodies; Autoimmunity; B-Cell Activation; B-Lymphocytes; Bacterial Infections; Cells; Clinical; Competence; Data; Development; Disease; Exhibits; Feedback; Flow Cytometry; Gene Expression; Genetic; Growth; HIV Infections; Hematopoietic; Human; IL4 gene; IgE; Immune; Immune response; Immune system; Immunity; Immunization; Individual; Infection; Injection of therapeutic agent; Interferon Type II; Interleukin-17; Interleukin-4; Knock-out; Knowledge; Lymphocyte; Mediating; Mediator of activation protein; Molecular; Mus; Mutation; Myeloid Cells; Parasites; Pathologic; Peripheral; Phenotype; Play; Production; Regulation; Reporting; Residual state; Role; Serum; Signal Transduction; Structure of germinal center of lymph node; Sum; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymus Gland; Transplantation; Virus Diseases; Whole Organism; base; cell type; computerized data processing; cytokine; design; immune function; improved; pathogen; prevent; programs; research study; response; thymocyte; transcription factor

Interleukin 4 (IL-4), which is produced by lymphocytes and myeloid cells, is an early multifunctional cytokine with profound effects on the immune system and the immune responses. Many of its effects are mediated through IgE antibodies. IL-4 affords host protection against infections with parasites, and it can prevent damaging autoimmunity, but it also potentially hinders protective immune responses against bacterial and viral infections, exacerbates allergic immune responses and enables anaphylactic reactivity. The production of IL-4 is regulated at multiple levels. Much is already known about the molecular control of IL-4 gene expression, as well as cellular interactions regulating IL-4 production in the course of an immune response. Here, IL-4 itself plays an important role in positive feedback control. In contrast, far less is known about regulatory mechanisms in the early development of cells capable of producing IL-4, especially innate cell types, which mature independently of IL-4 signals. The proposed project aims at elucidating this initial regulation, which, prior to any immune response, lays the tracks for later immune competence of the whole organism. We just reported that mice genetically deficient in certain γδ T cells (B6.Vγ4/6KO) exhibit pathologically increased IL-4-production, and a loss of B cell tolerance. The phenotype includes high levels of IgE before and after immunization, as well as further changes similar to those seen associated with pathologically high IgE antibodies in humans. In contrast, mice deficient in all γδ T cells are phenotypically normal, and the sum of our findings suggests that interactions between γδ T cell subsets determine early T cell differentiation into IL-4 competent cell-types, and eventually overall (background) IL-4 production in non-immunized mice. Moreover, we see a positive correlation between high background IL-4 and much stronger IgE responses following immunization. Here, we propose to investigate the cellular interactions that determine the IL-4 baseline. To probe crosstalk among γδ T cells and between γδ and αβ T cells, we will change it, by manipulating individual T cell subsets through genetic knockout, specific antibody treatment or cell transfer, and then analyze the effect on the remaining cells using multi-parameter flow cytometry and high-dimensional data processing, to test the hypothesis that crosstalk among γδ T cells and between γδ and αβ T cells in thymus and periphery determine the extent of innate IL-4 production and IL-4-driven immune responsiveness in normal healthy mice. We suspect that similar pre-immune mechanisms are operational in humans. Knowledge about how the IL-4 baseline is established might enable its manipulation, and the adjustment of immune responsiveness towards healthy levels.

白细胞介素4(IL-4)是一种早期的多功能细胞因子，由淋巴细胞和髓系细胞产生 对免疫系统和免疫反应有深远的影响。它的许多影响都是通过中介实现的 通过IgE抗体。IL-4为宿主提供了免受寄生虫感染的保护，它可以防止 破坏自身免疫，但也可能阻碍针对细菌和病毒的保护性免疫反应 感染，加剧过敏性免疫反应，并使过敏反应。白介素4的生产 在多个层面上受到监管。关于IL-4基因表达的分子控制，人们已经知道了很多，比如 以及在免疫反应过程中调节IL-4产生的细胞相互作用。在这里，IL-4本身 在正反馈控制中起着重要的作用。相比之下，人们对监管机制的了解要少得多 在能够产生IL-4的细胞的早期发育中，特别是在成熟的固有细胞类型中 不依赖于IL-4信号。拟议的项目旨在阐明这一初步规定，在任何 免疫反应，为后来整个生物体的免疫能力奠定了基础。 我们刚刚报道了某些γδT细胞(B6.Vγ4/6KO)基因缺陷的小鼠在病理上表现出 IL-4产生增加，B细胞耐受性丧失。表型包括以前和之前高水平的IgE 免疫后，以及与病理高IgE相关的进一步变化 人类体内的抗体。相反，所有γδT细胞缺陷的小鼠表型正常，我们的总和 研究结果表明，γδT细胞亚群之间的相互作用决定了T细胞早期分化为IL-4 合格的细胞类型，并最终在未免疫的小鼠中产生总的(背景)IL-4。此外， 我们发现高背景IL-4与以下更强的IgE反应呈正相关 免疫接种。在这里，我们建议研究决定IL-4基线的细胞相互作用。至 γδT细胞之间以及γδ和αβT细胞之间的探测串扰，我们将通过操作单个T细胞来改变它 通过基因敲除、特异性抗体处理或细胞转移等方法对细胞亚群进行处理，然后分析其效果 对剩余细胞采用多参数流式细胞术和高维数据处理，检测 胸腺和外周γδT细胞之间以及γδ和αβT细胞之间存在串扰的假说 测定正常人先天IL-4产生及IL-4免疫应答的程度 健康的老鼠。我们怀疑，类似的免疫前机制也在人类身上发挥作用。了解以下内容 IL-4基线是如何建立的，可能使其能够进行操纵，以及免疫调节 对健康水平的反应能力。