Decay accelerating factor dependent inhibition of T cell immunity

T 细胞免疫的衰变加速因子依赖性抑制

• 批准号: 9282415
• 负责人: DIRK HOMANN
• 金额: $ 21.19万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282415
• 关键词: Address; Alloantigen; Anaphylatoxins; Animals; Autoantigens; Autoimmune Diseases; Autoimmune Process; Biological; C3AR1 gene; CD55 Antigens; CD80 gene; CTLA4 gene; Cell surface; Cells; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Factor D; Data; Development; Disease; Down-Regulation; Eragrostis; Exhibits; Graft Rejection; Grant; Health; Hematopoietic; Homologous Gene; Hour; Human; Immune; Immune Tolerance; Immune response; Immunity; Inflammatory; Injury; Knowledge; LIF gene; Link; Literature; Modeling; Mus; Organ Transplantation; Outcome; Patients; Peptide/MHC Complex; Physiological; Process; Production; Proteins; Publishing; Reagent; Regulatory T-Lymphocyte; Reporting; Research; Solid; Surface; T cell response; T memory cell; T-Cell Receptor; T-Lymphocyte; TNFRSF5 gene; Testing; To autoantigen; Transgenic Mice; Transplantation; Viral; Virus; Virus Diseases; Work; adaptive immunity; anergy; cytokine; experimental study; high reward; high risk; improved; in vivo; inhibitor/antagonist; innovation; insight; killings; mouse model; novel; novel therapeutic intervention; novel therapeutics; pathogen; prevent; receptor; response; tool

Abstract Decay accelerating factor (DAF, CD55) is a glycophosphatidylinositol (GPI)-linked, cell surface-expressed protein with a known primary function as an intrinsic (on the cell surface on which it is expressed) regulator of complement cascade activation. We among others discovered that DAF crucially modulates T cell immune responses by locally regulating complement activation. We also showed that during cognate T cell/APC interactions surface DAF expression is rapidly (within hours) yet transiently (24-48h) downregulated. We hypothesize that this transient downregulation crucially permits local complement activation to drive induction of effector T cells (Teff) while simultaneously inhibiting induction, function and stability of regulatory T cells (Treg). While DAF deficient animals have been produced and exhibit enhanced T cell immune responses, formal testing of this hypothesis requires the ability to constitutively enforce stable DAF expression on immune cell surfaces in vivo. Our hypothesis predicts that this enforced DAF expression will inhibit APC activation and limit induction of Teff immunity and simultaneously will permit and facilitate Treg induction/stability, together dampening protective anti-viral T cell immunity while favoring immunological tolerance directed toward allo- or autoantigens. If our working model is correct, the findings will be conceptually innovative and significant in that they would support a novel mechanism that exerts control over T cell immunity in vivo. The proposed work will result in production of a mouse with an inducible, stable surface expressed form of DAF, thereby adding an essential missing tool to the toolbox of biological reagents available for studying links between adaptive immunity and complement activation. We propose to test this hypothesis in this R21 application through 2 aims: 1) To modulate T cell immunity by enforced DAF expression in hematopoietic cells and 2) To produce and analyze T cell immune responses in an inducible, conditional, DAF transgenic mouse. The findings derived from this “high-risk high-reward” R21 application are likely to provide new insight into the impact of DAF expression (rather than its absence) on in vivo T cell immune responses, an issue that has not been addressed and represents a gap in our current knowledge. If our working model is correct, the findings would provide the basis for novel therapeutic strategies to increase DAF expression in efforts to induce tolerogenic responses that prevent and/or treat autoimmune disease, transplant rejection and graft vs. host disease. In addition, at the completion of this R21 grant we will have produced novel biological tools including inducible DAF transgenic mice that will permit us to test DAF-dependent tolerogenic strategies in autoimmune and transplant models, determine whether and how DAF impacts induction of naïve and/or memory T cell activation and function in each situation, and provide insight into mechanisms underlying physiological DAF downregulation.

抽象的 衰减加速因子（DAF，CD55）是糖磷脂酰肌醇（GPI）连接，细胞表面表达 具有已知主要功能的蛋白质是固有的（在其表达的细胞表面上）调节剂的蛋白质 补充级联激活。我们等人发现DAF完全调节T细胞免疫 通过局部调节完成激活的响应。我们还表明，在同源T细胞/APC期间 相互作用表面DAF表达迅速（在几个小时内），但瞬时（24-48h）下调。我们 假设这种短暂下调完全允许局部完成激活驱动诱导 效应T细胞（TEFF）同时抑制调节T细胞的诱导，功能和稳定性 （Treg）。虽然已经产生了DAF缺乏动物并暴露了增强的T细胞免疫反应，但 对该假设的正式检验需要对免疫的稳定DAF的组成构成能力 体内细胞表面。我们的假设预测，这种强制执行的DAF表达将抑制APC激活和 限制TEFF免疫的诱导，仅允许并促进Treg诱导/稳定性 抑制防护性抗病毒T细胞免疫霍斯托，同时有利于针对同种或同种的免疫耐受性 自动抗原。如果我们的工作模型是正确的，那么这些发现将在概念上具有创新性和意义 他们将支持一种新的机制，该机制可以控制体内T细胞免疫。拟议的工作将 导致产生具有诱导稳定表达的DAF形式的小鼠，从而增加 可用于研究自适应之间的链接的生物试剂工具箱的必不可少的工具 免疫力和完成激活。我们建议在此R21应用程序中检验这一假设 目的：1）通过在造血细胞中强制执行DAF表达来调节T细胞免疫，2） 并分析T细胞免疫复杂，以诱导的条件，DAF转基因小鼠。发现得出 从这个“高风险高级” R21应用程序中，R21的应用可能可以提供有关DAF影响的新见解 体内T细胞免疫调查中的表达（而不是其缺席），这一问题尚未解决 并代表我们当前知识的差距。如果我们的工作模型正确，发现将提供 新型治疗策略的基础，以增加DAF表达以诱导公差反应 这可以预防和/或治疗自身免疫性疾病，移植排斥和移植与宿主疾病。另外，at 这笔R21赠款的完成，我们将生产出新的生物学工具，包括诱导DAF 转基因小鼠将使我们能够在自身免疫和移植中测试DAF依赖性的耐受性策略 模型，确定DAF是否以及如何影响幼稚和/或记忆T细胞激活的诱导以及 在每种情况下的功能，并深入了解物理DAF下调的机制。