The non-canonical NF-kappaB pathway in survival and function of T lymphocytes

T 淋巴细胞存活和功能中的非经典 NF-kappaB 通路

• 批准号: 8653526
• 负责人: DAVID C PARKER
• 金额: $ 38.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653526
• 关键词: Animals; Antigen Receptors; Antigens; Apoptotic; Applications Grants; Autoimmune Diseases; B-Lymphocytes; Biological Markers; Biological Models; Cell Line; Cell Survival; Cell model; Cell physiology; Cells; Chronic; Cytokine Receptors; Data; Effector Cell; Enzymes; Family; Family member; Generations; Graft Rejection; Hypersensitivity; Immune; Immune response; Immunity; Immunologic Receptors; In Vitro; Infection; Infectious Agent; Inflammation; Ligation; Lymphocyte; Lymphoid; Maintenance; Mammals; Measures; Memory; Methods; Mus; NF-kappa B; Organ; Pathway interactions; Pharmaceutical Preparations; Proliferating; Proteins; Reaction; Recombinants; Refractory; Regulation; Regulatory T-Lymphocyte; Role; Signal Pathway; Signal Transduction; Staging; Syndrome; System; T cell differentiation; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; TNFRSF8 gene; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Tumor Necrosis Factor Receptor; Vaccines; Work; cancer immunotherapy; cytokine; design; dimer; fly; graft vs host disease; high voltage electron microscopy; in vivo; member; microbial; overexpression; prototype; public health relevance; receptor; research study; response

DESCRIPTION (provided by applicant): In lymphocytes, signals from antigen, cytokine, and innate immune receptors cause immediate, transient activation of NF-:B through the canonical pathway by triggering IkB degradation. A second, non-canonical or "alternative" NF-kB pathway has been described downstream of some members of the TNFR family. Slow, sustained activation of NF-kB through this IkB-independent, NIK-dependent non-canonical pathway governs the formation of secondary lymphoid organs (downstream of LT2R) and determines the fate of B cells (downstream of BAFFR). Almost nothing is known of the role of the non-canonical NF-kB pathway in T cell function, although T cells express a number of costimulatory TNFR family members, including OX40, 4-1BB, CD27, GITR, CD30, and HVEM, that have been shown to activate the non-canonical pathway in transfected cell lines, and that are known to provide essential signals for function and survival of activated T cells after antigen recognition. The working hypothesis of this proposal is that sustained activation of NF-kB through the non-canonical pathway downstream of these TNFR family members is necessary for induction and maintenance of expression of the cytokines, cytokine receptors, and anti-apoptotic proteins that allow T cells to survive and function as differentiated effector and memory cells. The proposed experiments are designed to determine whether the non-canonical pathway is activated downstream of the costimulatory TNFR family members in T cells, whether it is necessary for the costimulatory activity of TNFR family members in vivo, and whether independent activation of that pathway mimics some of the costimulatory activities of the TNFR family members, including blocking the function of regulatory T cells.

描述(由申请人提供)：在淋巴细胞中，来自抗原、细胞因子和先天免疫受体的信号通过典型途径引发IKB降解，立即、短暂地激活核因子-B。在TNFR家族的一些成员下游，已经描述了第二个非典范或“替代”的NF-kB途径。通过这种IKB非依赖、NIK依赖的非规范途径缓慢、持续地激活NF-kB，控制着次级淋巴器官(LT2R下游)的形成，并决定B细胞(BAFFR下游)的命运。尽管T细胞表达许多共刺激的TNFR家族成员，包括OX40、4-1BB、CD27、GITR、CD30和HVEM，但几乎没有人知道非规范的NF-kB途径在T细胞功能中的作用，这些成员被证明在转基因细胞系中激活了非规范的途径，并被认为是在抗原识别后为激活的T细胞的功能和生存提供必要的信号。这一建议的工作假设是，通过这些TNFR家族成员下游的非规范途径持续激活NF-kB，对于诱导和维持细胞因子、细胞因子受体和抗凋亡蛋白的表达是必要的，这些蛋白允许T细胞存活并作为分化的效应细胞和记忆细胞发挥作用。这些实验旨在确定T细胞中非正则途径是否在共刺激的TNFR家族成员下游被激活，它是否是体内TNFR家族成员的共刺激活性所必需的，以及该途径的独立激活是否模仿了TNFR家族成员的一些共刺激活动，包括阻断调节性T细胞的功能。