Role of E3 Ubiquitin ligase RNF133 in T cell function and tolerance

E3 泛素连接酶 RNF133 在 T 细胞功能和耐受性中的作用

• 批准号: 10311074
• 负责人: Roza Insafetdinovna Nurieva
• 金额: $ 40万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311074
• 关键词: Address; Age; Age-Months; Antibodies; Antigens; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; CD4 Positive T Lymphocytes; Cell physiology; Cells; Development; Disease; Ensure; Exhibits; Experimental Autoimmune Encephalomyelitis; Generations; Genes; Genetic; Goals; Helper-Inducer T-Lymphocyte; Homologous Gene; IgG1; Immune Tolerance; Immunoglobulin G; In Vitro; Inflammation; Inflammatory; Interleukins; Invaded; Knock-out; Knockout Mice; Knowledge; Lead; Lymphocyte Activation; Lymphoid Tissue; Maintenance; Mediating; Methods; Modeling; Molecular; Pathogenicity; Peptides; Peripheral; Pharmacology; Phase; Phenotype; Physiological; Prevention; Production; Property; Protein Array Analysis; Proteins; Reagent; Regulation; Regulatory T-Lymphocyte; Research; Role; Self Tolerance; Signal Transduction; Symptoms; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Tumor stage; Work; Yeasts; adaptive immune response; base; cytokine; early onset; in vivo; insight; knock-down; oral tolerance; pathogen; peripheral tolerance; prevent; programs; response; screening; ubiquitin-protein ligase; yeast two hybrid system

PROJECT SUMMARY/ABSTRACT CD4+ T cells are the master regulators of adaptive immune responses, and a breakdown of self-tolerance in CD4+ cells leads to many autoimmune diseases. Understanding of the mechanisms underlying T cell tolerance will provide new significant insight in advancing our knowledge on the signaling and genetic controls of T helper (TH) cell tolerance programs that may have therapeutic implications for inflammatory diseases. Recently, we have acknowledged the essential role of GRAIL in immunological tolerance. Despite the critical role of GRAIL in T cell tolerance, GRAIL knockout (KO) mice do not spontaneously develop autoimmunity at early age, suggesting that closely-related protein(s) to GRAIL could contribute to control of the early onset of inflammation. Interestingly, among the five GRAIL homologs, RNF133 shows the highest expression in tolerant T cells, suggesting that RNF133 along with GRAIL could contribute to establishment of T cell tolerance; however its role in T cells has not been studied. RNF133 KO CD4+ T cells activated in vitro and in vivo under tolerogenic conditions exhibited enhanced level of proliferation and cytokine (interleukin (IL)-17 and IL-21) production compared to wild-type (WT) T cells, indicating the potential role of RNF133 in controlling TH (TH17 and T follicular (Tfh)) cell responses. In fact, RNF133 KO mice have elevated levels of IgG and IgG1 in the sera and percentage of TH17 and Tfh cells in the peripheral lymphoid tissues as early as 12 weeks of age followed by rise of autoimmune symptoms at 5-6 months of age. Moreover, RNF133 expression in regulatory T cells (Tregs) is essential to maintain their suppressive function, as well as stability and prevents them from acquiring pathogenic TH17 phenotype, suggesting that RNF133 functions to control pathogenic TH cell responses. Based on this, we hypothesize that RNF133 may be an important checkpoint molecule in maintaining immunological tolerance and in preventing the onset and development of inflammation. In Aim 1, we propose to determine the molecular mechanisms responsible for regulation and function of RNF133 in T cell tolerance by utilizing conditional gene knockdown approaches and in vivo T cell tolerance models. In Aim 2, we will determine the role of RNF133 in Tfh cell tolerance and underlying mechanisms as well. In addition, we will assess the mechanisms whereby RNF133 controls antibody-mediated autoimmunity. In Aim 3, we will determine the mechanism(s) by which RNF133 regulates Tregs and TH17 cell programming and stability. The physiological significance of this finding will be assessed in an experimental allergic encephalomyelitis (EAE) model. We will employ yeast two-hybrid screening and reverse phase protein array assay to identify the exact target(s) of RNF133, which determines its function in TH programming. The proposed research will provide new significant insight into characterization of mechanisms underlying T cell tolerance that will lead to development of pharmacological approaches to promote the tolerance state in terms of autoimmunity.

项目摘要/摘要 CD4+ T细胞是自适应免疫反应的主要调节剂，并且是自我耐受性的分解 CD4+细胞导致许多自身免疫性疾病。了解T细胞耐受性的机制 将提供新的重要见解，以促进我们对T的信号传导和遗传控制的了解 助手（TH）细胞耐受性程序可能对炎症性疾病具有治疗意义。 最近，我们认识到圣杯在免疫耐受性中的重要作用。尽管有 Grail在T细胞耐受性，Grail敲除（KO）小鼠中的关键作用不会自发发展 在幼年时期的自身免疫性，表明与圣杯密切相关的蛋白质可能有助于控制 炎症的早期发作。有趣的是，在这五个Grail同源物中，RNF133显示出最高的 耐受性T细胞中的表达，表明RNF133与圣杯一起可能有助于建立T 细胞耐受性；但是，尚未研究其在T细胞中的作用。 RNF133 KO CD4+ T细胞在体外激活，并且 在耐受性条件下体内表现出增殖水平增强和细胞因子（白介素（IL）-17） 与野生型（WT）T细胞相比，IL-21）产生的产生，表明RNF133在控制中的潜在作用 Th（Th17和T卵泡（TFH））细胞反应。实际上，RNF133 KO小鼠的IgG和IgG1水平升高 在周围淋巴组织中Th17和TFH细胞的血清和百分比中 年龄在5-6个月大时出现自身免疫性症状的升高。此外，RNF133在 调节性T细胞（Tregs）对于维持其抑制功能以及稳定性至关重要 它们是从获取致病性Th17表型中的，这表明RNF133功能控制致病 细胞反应。基于此，我们假设RNF133可能是重要的检查点分子 保持免疫学耐受性并防止炎症的发作和发展。 在AIM 1中，我们建议确定负责调节和功能的分子机制 通过使用条件基因敲低方法和体内T细胞耐受性，T细胞耐受性的RNF133 型号。在AIM 2中，我们将确定RNF133在TFH细胞耐受性和潜在机制中的作用 出色地。此外，我们将评估RNF133控制抗体介导的自身免疫性的机制。 在AIM 3中，我们将确定RNF133调节Treg和Th17细胞的机制 编程和稳定性。该发现的生理意义将在实验中评估 过敏性脑脊髓炎（EAE）模型。我们将采用酵母双杂交筛选和反向相蛋白 数组测定以识别RNF133的确切目标，该目标确定其在TH编程中的功能。 拟议的研究将为机制的表征提供新的重要洞察力 潜在的T细胞耐受性将导致促进药理方法的发展 自身免疫性方面的公差状态。

项目成果

Distinct Immunophenotypes of T Cells in Bronchoalveolar Lavage Fluid From Leukemia Patients With Immune Checkpoint Inhibitors-Related Pulmonary Complications.

• DOI: 10.3389/fimmu.2020.590494
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Kim ST;Sheshadri A;Shannon V;Kontoyiannis DP;Kantarjian H;Garcia-Manero G;Ravandi F;Im JS;Boddu P;Bashoura L;Balachandran DD;Evans SE;Faiz S;Ruiz Vazquez W;Divenko M;Mathur R;Tippen SP;Gumbs C;Neelapu SS;Naing A;Wang L;Diab A;Futreal A;Nurieva R;Daver N
• 通讯作者: Daver N