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

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。 公共卫生相关性：这项拨款申请建议测试T细胞在看到其抗原后需要特定的细胞内信号通路(非规范的核因子-kB途径)以使其存活和发挥功能的想法。T细胞中这一途径的激活可以作为有效疫苗的早期生物标志物，以及扭转T细胞在慢性感染和癌症免疫治疗中无反应性的方法。通过抑制这一途径中的酶的药物(IKK1和/或NIK)有可能阻止正在进行的免疫反应，这些反应依赖于炎症和组织损伤引起的内部危险信号，如变态反应、自身免疫病、移植排斥反应和移植物抗宿主病，而不会通过相关途径(典型的核因子-kB途径)和其他信号途径阻止对由微生物产物的抗原受体和固有受体驱动的感染性物质的免疫。

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.