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触发IkB降解，引起NF-:B的立即、短暂激活。第二种非规范或“替代”NF-kB通路已在一些TNFR家族成员的下游被描述。NF-kB通过这种不依赖于ikb、依赖于nik的非典型途径缓慢、持续地激活，控制次级淋巴器官（LT2R的下游）的形成，并决定B细胞（BAFFR的下游）的命运。尽管T细胞表达了许多共刺激TNFR家族成员，包括OX40、4-1BB、CD27、GITR、CD30和HVEM，但人们对非规范NF-kB通路在T细胞功能中的作用几乎一无所知，这些成员已被证明可以激活转染细胞系中的非规范通路，并且已知它们在抗原识别后为活化T细胞的功能和存活提供必要的信号。该建议的工作假设是，通过这些TNFR家族成员下游的非规范途径，NF-kB的持续激活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效应细胞和记忆细胞发挥作用。本实验旨在确定非规范通路是否在T细胞共刺激TNFR家族成员下游被激活，是否为体内TNFR家族成员共刺激活性所必需，以及该通路的独立激活是否模拟TNFR家族成员的某些共刺激活性，包括阻断调节性T细胞的功能。

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.