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细胞有效地对外国抗原做出反应，但对自我入狱和正常肠菌群具有耐受性。 T细胞的不当激活或分化会导致严重的免疫疾病，包括自身免疫性和炎症。因此，对调节T细胞激活和耐受性的分子机制的更好理解对于免疫疾病的理性设计很重要。该应用的总体目的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性炎症的分子和细胞机制。在当前的资金期间，我们进行了开创性的发现，以CYLD为T细胞激活和自身免疫性炎症的关键调节剂。 CYLD缺陷型T细胞对TCR刺激具有高反应性，CYLD基因敲除（CYLD - / - ）小鼠自发发展肠道炎症，具有人类炎症性肠病（IBD）的主要特征。 CYLD - / - 小鼠还经历了严重的骨质流失，这被称为IBD的主要肠外并发症和结肠炎动物模型。此外，我们的初步研究表明，CYLD的丧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性疾病的主要调节剂。 在此连续应用中提出的研究基于我们实验室的强大初步和已发布的数据。特别是，我们已经表明，T细胞中CYLD的丧失会导致NF-KB的组成型激活，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细胞还显示了共刺激分子ICO的明显衰减，这对于诱导T细胞耐受性和T细胞分化的调节至关重要。与这些分子研究一致，我们发现CYLD - / - T细胞似乎在容忍肠性微生物方面有缺陷，因为它们的产卵转移到缺乏淋巴细胞的RAG1 - / - 小鼠中会诱导严重的结肠炎。此外，CYLD - / - 小鼠产生异常高的炎症性Th17和Th1细胞，并与EAE反应增强相结合。我们获得了初步证据，表明CYLD调节对TLR刺激的巨噬细胞反应，该表达的特定细胞因子已知的调节Th1和Th17分化的特定子集。基于这些发现，我们假设CYLD调节与T细胞激活和分化以及耐受性诱导有关的关键信号事件。我们将执行三个特定的目标来实现我们的整体目标。 （1）检查T细胞中CYLD介导的NF-KB调节的分子机制和功能意义。 （2）表征CYLD调节T细胞耐受性和炎症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部机制。 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而导致的失调的T细胞激活会导致严重的免疫疾病，包括自身免疫性和慢性炎症。该研究项目的重点是了解去泛素酶，CYLD如何调节T细胞激活和耐受性，从而防止自身免疫性和炎症的发展。这种知识对于有效的免疫疗法的合理设计很重要。