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

描述（由申请方提供）：在淋巴细胞中，来自抗原、细胞因子和先天性免疫受体的信号通过经典途径触发Ik B降解，引起NF-：B的立即、短暂激活。第二种非经典或“替代性”NF-kB途径已经在TNFR家族的一些成员的下游被描述。NF-κ B通过这种IkB非依赖性、NIK依赖性非经典途径的缓慢、持续活化控制次级淋巴器官的形成（LT 2 R下游），并决定B细胞的命运（BAFFR下游）。尽管T细胞表达许多共刺激性TNFR家族成员，包括OX 40、4-1BB、CD 27、GITR、CD 30和HVEM，但几乎不知道非经典NF-kB途径在T细胞功能中的作用，这些共刺激性TNFR家族成员已显示在转染的细胞系中激活非经典途径，并且已知其在抗原识别后为活化的T细胞的功能和存活提供必需的信号。该提议的工作假设是，通过这些TNFR家族成员下游的非经典途径持续激活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，所述细胞因子、细胞因子受体和抗凋亡蛋白允许T细胞存活并作为分化的效应细胞和记忆细胞发挥功能。所提出的实验旨在确定非经典途径是否在T细胞中的共刺激TNFR家族成员的下游被激活，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拟TNFR家族成员的一些共刺激活性，包括阻断调节性T细胞的功能。 公共卫生相关性：该拨款申请提出测试以下想法：在T细胞看到其抗原后，特定的细胞内信号传导途径（非经典NF-kB途径）在T细胞中是必需的，以允许它们存活和发挥功能。T细胞中这种途径的激活可以作为有效疫苗的早期生物标志物，以及逆转慢性感染和癌症免疫治疗中T细胞无反应性的方法。通过药物特异性作用于该途径中的酶来抑制该途径（IKK 1和/或NIK）具有阻断正在进行的免疫反应的潜力，所述免疫反应依赖于由炎症和组织损伤引起的内部危险信号，例如过敏、自身免疫性疾病、移植排斥和移植物抗宿主病，而不阻断通过相关途径（经典NF-kB途径）和其它信号传导途径由抗原受体和微生物产物的先天受体驱动的对感染因子的免疫。

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.