Regulation of T-cell function and autoimmune inflammation by deubiquitinase CYLD

去泛素酶 CYLD 对 T 细胞功能和自身免疫炎症的调节

• 批准号: 8289618
• 负责人: Shao-Cong Sun
• 金额: $ 48.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289618
• 关键词: Adoptive Transfer; Animal Model; Antigens; Attenuated; Autoimmune Process; Autoimmunity; Biochemical; Bone Marrow; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Colitis; Complication; Coupled; Data; Deubiquitination; Development; Disease; Enteral; Environmental Risk Factor; Event; Experimental Autoimmune Encephalomyelitis; Funding; Gene Expression Regulation; Genetic; Homeostasis; Human; ITGAM gene; Immune System Diseases; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Link; Lymphocyte; Lysine; Mediating; Microbe; Molecular; Mus; NF-kappa B; Normal tissue morphology; Osteoclasts; Osteopenia; Osteoporosis; Patients; Phosphotransferases; Population; Production; Publishing; Rag1 Mouse; Regulation; Regulatory T-Lymphocyte; Research Project Grants; Role; Seminal; Signal Transduction; Spleen; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Th1 Cells; Ubiquitin; Ubiquitination; Work; attenuation; base; bone; bone loss; cytokine; design; experience; macrophage; microbial; osteoclastogenesis; prevent; public health relevance; response; therapy design; transcription factor; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): T cells effectively respond to foreign antigens but are tolerant to self-tissues and normal enteric flora. Inappropriate activation or differentiation of T cells can lead to severe immunological disorders, including autoimmunity and inflammation. Thus, a better understanding of the molecular mechanisms regulating T-cell activation and tolerance is important for rational design of therapies for immunological diseases. The overall objective of this application is to understand the molecular and cellular mechanisms by which a newly identified deubiquitinase (DUB), CYLD, regulates T-cell function and autoimmune inflammation. During the current funding period, we have made seminal findings that establish CYLD as a pivotal regulator of T-cell activation and autoimmune inflammation. CYLD-deficient T cells are hyper-responsive to TCR stimulation, and the CYLD knockout (CYLD-/-) mice spontaneously develop intestinal inflammation with major features of human inflammatory bowel disease (IBD). The CYLD-/- mice also experience severe bone loss, which is known as a major extra-intestinal complication of IBD and animal model of colitis. Moreover, our preliminary studies reveal that loss of CYLD renders mice hypersensitive to the induction of experimental autoimmune encephalomyelitis (EAE). Thus, CYLD is a master regulator of T-cell function and autoimmune inflammatory diseases. The studies proposed in this continuation application are based on strong preliminary and published data from our laboratory. In particular, we have shown that loss of CYLD in T cells causes constitutive activation of NF-kB, a transcription factor mediating T-cell activation and survival and being involved in many inflammatory disorders. The CYLD-/- T cells also display marked attenuation of the costimulatory molecule ICOS, which is crucial for the induction of T-cell tolerance and regulation of T-cell differentiation. Consistent with these molecular studies, we have found that the CYLD-/- T cells appear to be defective in tolerance to enteric microbes, since their adoptive transfer into lymphocyte-deficient Rag1-/- mice induces severe colitis. Furthermore, the CYLD-/- mice produce aberrantly high levels of inflammatory Th17 and Th1 cells, coupled with heightened EAE response. We have obtained preliminary evidence that CYLD regulates macrophage response to TLR-stimulated expression of a specific subset of cytokines known to regulate Th1 and Th17 differentiation. Based on these findings, we hypothesize that CYLD regulates key signaling events involved in T-cell activation and differentiation as well as tolerance induction. We will perform three specific aims to accomplish our overall objective. (1) Examine the molecular mechanism and functional significance of CYLD-mediated NF-kB regulation in T cells. (2) Characterize the molecular and cellular mechanisms by which CYLD regulate T-cell tolerance and inflammatory T-cell differentiation. (3) Examine the immunological and osteoclast-intrinsic mechanisms by which CYLD regulates bone erosion. PUBLIC HEALTH RELEVANCE: T cells are vital for immune responses against microbial infections. However, deregulated T cell activation, due to genetic or environmental factors, can lead to severe immunological disorders, including autoimmunity and chronic inflammation. The focus of this research project is to understand how a deubiquitinase, CYLD, regulates T-cell activation and tolerance, thereby preventing the development of autoimmunity and inflammation. This knowledge is important for rational design of effective immunological therapies.

描述（由申请人提供）：T 细胞有效对外源抗原作出反应，但对自身组织和正常肠道菌群具有耐受性。 T 细胞的不当激活或分化可导致严重的免疫紊乱，包括自身免疫和炎症。因此，更好地了解调节 T 细胞激活和耐受的分子机制对于合理设计免疫疾病疗法非常重要。该应用的总体目标是了解新鉴定的去泛素酶 (DUB) CYLD 调节 T 细胞功能和自身免疫炎症的分子和细胞机制。在当前资助期间，我们取得了开创性的发现，将 CYLD 确立为 T 细胞激活和自身免疫炎症的关键调节因子。 CYLD 缺陷的 T 细胞对 TCR 刺激反应过度，CYLD 敲除 (CYLD-/-) 小鼠会自发产生肠道炎症，其主要特征是人类炎症性肠病 (IBD)。 CYLD-/-小鼠还经历严重的骨质流失，这被认为是IBD和结肠炎动物模型的主要肠外并发症。此外，我们的初步研究表明，CYLD 的缺失使小鼠对实验性自身免疫性脑脊髓炎 (EAE) 的诱导过敏。因此，CYLD 是 T 细胞功能和自身免疫炎症性疾病的主要调节因子。 本延续申请中提出的研究基于我们实验室强有力的初步和已发表的数据。特别是，我们已经证明，T 细胞中 CYLD 的丢失会导致 NF-kB 的组成性激活，NF-kB 是介导 T 细胞激活和存活的转录因子，并参与许多炎症性疾病。 CYLD-/- T细胞还表现出共刺激分子ICOS的显着减弱，这对于诱导T细胞耐受和调节T细胞分化至关重要。与这些分子研究一致，我们发现 CYLD-/- T 细胞似乎对肠道微生物的耐受性有缺陷，因为它们过继转移到淋巴细胞缺陷的 Rag1-/- 小鼠中会诱发严重的结肠炎。此外，CYLD-/- 小鼠产生异常高水平的炎症 Th17 和 Th1 细胞，同时 EAE 反应增强。我们已经获得了初步证据，表明 CYLD 调节巨噬细胞对 TLR 刺激的已知调节 Th1 和 Th17 分化的特定细胞因子子集表达的反应。基于这些发现，我们假设 CYLD 调节涉及 T 细胞激活和分化以及耐受诱导的关键信号转导事件。我们将实现三个具体目标来实现我们的总体目标。 (1) 研究CYLD介导的T细胞NF-kB调节的分子机制和功能意义。 (2) 表征CYLD调节T细胞耐受和炎症T细胞分化的分子和细胞机制。 (3) 检查CYLD调节骨侵蚀的免疫学和破骨细胞内在机制。 公共卫生相关性：T 细胞对于针对微生物感染的免疫反应至关重要。然而，由于遗传或环境因素，T 细胞激活失调可能导致严重的免疫疾病，包括自身免疫和慢性炎症。该研究项目的重点是了解去泛素酶 CYLD 如何调节 T 细胞激活和耐受，从而防止自身免疫和炎症的发展。这些知识对于合理设计有效的免疫疗法非常重要。