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: 8261672
• 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/8261672
• 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. PUBLIC HEALTH RELEVANCE: This grant application proposes to test the idea that a particular intracellular signaling pathway (the non- canonical NF-kB pathway) is necessary in T cells after they see their antigen to allow them to survive and function. Activation of this pathway in T cells could serve as an early biomarker for effective vaccines and a method to reverse T cell unresponsiveness in chronic infections and cancer immunotherapy. Inhibition of this pathway by drugs acting specifically on enzymes in this pathway (IKK1 and/or NIK) has the potential to block ongoing immune reactions that are dependent on internal danger signals resulting from inflammation and tissue damage, such as allergy, autoimmune disease, transplant rejection, and graft-versus-host disease, without blocking immunity to infectious agents driven by antigen receptors and innate receptors for microbial products through a related pathway (the canonical NF-kB pathway) and other signaling pathways.

描述（由申请人提供）：在淋巴细胞，抗原，细胞因子和先天免疫受体的信号中，通过触发IKB降解，通过规范途径引起NF-：B的瞬时激活。已经描述了TNFR家族的一些成员的第二个非典型或“替代” NF-KB途径。 NF-KB通过这种独立于IKB的NIK依赖性非统计途径的缓慢，持续的激活决定了次级淋巴机构的形成（LT2R的下游），并决定了B细胞的命运（BAFFR的下游）。尽管T细胞表达了许多共刺激性TNFR家族成员，包括OX40、4-1BB，CD27，GITR，CD30和HVEM，但几乎什么都不知道，尽管T细胞表达了许多共刺激性TNFR家族成员的作用，尽管已被证明可激活了在已知的细胞中激活的细胞，并且在均可激活的单元格中，这些途径均可以为无效的细胞而生存。该提案的工作假设是，NF-KB通过这些TNFR家族成员下游的非人道途径的持续激活对于诱导和维持细胞因子的表达，细胞因子受体和抗凋亡蛋白的表达是必要的，该蛋白使T细胞可以作为分化的效应和记忆细胞的生存和作用。 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. 公共卫生相关性：该赠款的应用建议测试特定细胞内信号通路（非规范NF-KB途径）在T细胞看到其抗原使其能够生存和功能之后，必须在T细胞中进行特定的细胞内信号通路（非规范NF-KB途径）。该途径在T细胞中的激活可以作为有效疫苗的早期生物标志物，也可以作为一种在慢性感染和癌症免疫疗法中反应反应的方法。 Inhibition of this pathway by drugs acting specifically on enzymes in this pathway (IKK1 and/or NIK) has the potential to block ongoing immune reactions that are dependent on internal danger signals resulting from inflammation and tissue damage, such as allergy, autoimmune disease, transplant rejection, and graft-versus-host disease, without blocking immunity to infectious agents driven by antigen receptors and innate通过相关途径（规范NF-KB途径）和其他信号通路的微生物产物受体。