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.

项目概要/摘要 CD4+ T 细胞是适应性免疫反应的主要调节者，也是自我耐受性崩溃的主要调节者。 CD4+细胞会导致许多自身免疫性疾病。了解 T 细胞耐受的机制 将为增进我们对 T 信号传导和遗传控制的了解提供新的重要见解 辅助（TH）细胞耐受程序可能对炎症性疾病具有治疗意义。 最近，我们认识到 GRAIL 在免疫耐受中的重要作用。尽管 GRAIL 在 T 细胞耐受中发挥关键作用，GRAIL 敲除 (KO) 小鼠不会自发发育 幼年时的自身免疫，表明与 GRAIL 密切相关的蛋白质可能有助于控制 炎症早期发作。有趣的是，在五个 GRAIL 同源物中，RNF133 显示出最高的 在耐受性 T 细胞中表达，表明 RNF133 与 GRAIL 可能有助于 T 细胞的建立 细胞耐受性；然而，其在 T 细胞中的作用尚未被研究。 RNF133 KO CD4+ T 细胞在体外激活 在体内耐受条件下表现出增殖水平和细胞因子（白细胞介素（IL）-17 和 IL-21）产量与野生型 (WT) T 细胞相比，表明 RNF133 在控制中的潜在作用 TH（TH17 和滤泡 T (Tfh)）细胞反应。事实上，RNF133 KO 小鼠的 IgG 和 IgG1 水平升高 早在接种第 12 周时，血清中的 TH17 和 Tfh 细胞以及外周淋巴组织中的 TH17 和 Tfh 细胞百分比 随着年龄的增长，自身免疫症状会在 5-6 个月大时出现。此外，RNF133 表达于 调节性 T 细胞 (Treg) 对于维持其抑制功能以及稳定性和防止 它们获得致病性 TH17 表型，表明 RNF133 具有控制致病性 TH 的功能 细胞反应。据此，我们推测RNF133可能是体内重要的检查点分子。 维持免疫耐受并预防炎症的发生和发展。 在目标 1 中，我们建议确定负责调节和功能的分子机制。 利用条件基因敲除方法和体内 T 细胞耐受性，RNF133 在 T 细胞耐受性中的作用 模型。在目标 2 中，我们将确定 RNF133 在 Tfh 细胞耐受中的作用和潜在机制： 出色地。此外，我们将评估 RNF133 控制抗体介导的自身免疫的机制。 在目标 3 中，我们将确定 RNF133 调节 Tregs 和 TH17 细胞的机制 编程和稳定性。这一发现的生理意义将在实验中进行评估 过敏性脑脊髓炎（EAE）模型。我们将采用酵母双杂交筛选和反相蛋白 阵列分析来识别 RNF133 的确切靶点，从而确定其在 TH 编程中的功能。 拟议的研究将为机制表征提供新的重要见解 潜在的 T 细胞耐受性将导致药理学方法的发展以促进 自身免疫方面的耐受状态。

项目成果

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

来自与免疫检查点抑制剂相关肺并发症的白血病患者的支气管肺泡灌洗液中T细胞的独特免疫表型。

• 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