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.

项目总结/文摘

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