Control of IL-4 by gamma/delta T Cells

γ/δ T 细胞对 IL-4 的控制

• 批准号: 9307703
• 负责人: WILLI K BORN
• 金额: $ 20.3万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307703
• 关键词: Adult; Affect; Allergic; Antibodies; Autoimmunity; B-Cell Activation; B-Lymphocytes; Bacterial Infections; Cells; Clinical; 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; Immunocompetence; 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; experimental study; high dimensionality; immune function; improved; pathogen; prevent; response; thymocyte; transcription factor; γδ T cells

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）是由淋巴细胞和髓系细胞产生的一种早期多功能细胞因子 对免疫系统和免疫反应有着深远的影响。它的许多影响是通过 通过IgE抗体。IL-4可保护宿主免受寄生虫感染， 破坏自身免疫，但它也可能阻碍对细菌和病毒的保护性免疫反应， 感染，加剧过敏性免疫应答并使过敏反应性成为可能。IL-4的产生 在多个层面上受到监管。关于IL-4基因表达的分子控制已经知道很多， 以及在免疫应答过程中调节IL-4产生的细胞相互作用。IL-4本身 在正反馈控制中起着重要的作用。相比之下，人们对调控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，尤其是成熟的先天细胞类型 与IL-4信号无关。拟议的项目旨在阐明这一初步规定， 免疫反应，奠定了整个生物体的免疫能力。 我们刚刚报道了某些γδ T细胞遗传缺陷小鼠（B6.Vγ4/6 KO）的病理表现， IL-4产生增加和B细胞耐受性丧失。表型包括高水平的IgE之前， 免疫后，以及与病理性高IgE相关的进一步变化 人体内的抗体相比之下，所有γδ T细胞缺陷的小鼠表型正常，并且我们的 研究结果表明，γδ T细胞亚群之间的相互作用决定了早期T细胞分化为IL-4 感受态细胞类型，并最终在非免疫小鼠中产生总体（背景）IL-4。此外，委员会认为， 我们看到高背景IL-4与以下更强的IgE反应之间存在正相关性 次免疫在这里，我们建议调查确定IL-4基线的细胞相互作用。到 为了探测γδ T细胞之间以及γδ和αβ T细胞之间的串扰，我们将通过操纵单个T细胞来改变它， 细胞亚群通过基因敲除、特异性抗体处理或细胞转移，然后分析效果 对剩余的细胞采用多参数流式细胞仪和高维数据处理，以检测 胸腺及外周γδ T细胞间及γδ与αβ T细胞间相互作用假说 确定正常人先天性IL-4产生和IL-4驱动的免疫应答的程度， 健康的老鼠我们怀疑类似的免疫前机制在人类中也是可行的。知识 如何建立IL-4基线可能使其操作，以及免疫调节 达到健康水平。