The Alternative NFkB Pathway in Survival and Function of Anti-Viral T Cells

描述（由申请人提供）：NFkB系统是一种古老的细胞内信号传导途径，可协调蠕虫、苍蝇和哺乳动物等多种动物对感染的炎症免疫反应。在淋巴细胞中，来自抗原和细胞因子受体的信号通过触发IkB降解的经典途径引起NF kB的急性和短暂活化。通过一组选定的细胞因子受体（包括TNFR家族的一些成员）进行刺激，通过IkB非依赖性、NIK依赖性旁路途径引起NFkB的持续激活。这种替代的NF κ B活化途径最近已被证明控制次级淋巴器官的形成并决定新分化的B细胞的命运，但其在T细胞中的功能尚不清楚。该提议的工作假设是，响应于晚期共刺激信号，增殖T细胞中替代NFkB途径的持续激活诱导并维持细胞因子、细胞因子受体和抗凋亡蛋白的表达，这些蛋白是应答T细胞作为分化的效应细胞发挥作用并作为记忆细胞存活所必需的。我们将测试这一假设，使用小鼠T细胞是在替代NFkB途径缺陷，以确定替代途径是否是必要的T细胞分化为效应细胞和生存的免疫应答淋巴细胞性脉络丛脑膜炎病毒的长寿记忆细胞。使用逆转录病毒转导和Cre诱导的转基因在T细胞中表达旁路途径的活性成分，我们将确定当共刺激信号受限时，旁路途径的激活是否足以产生效应和记忆T细胞。本申请中提出的实验可以证明替代NFkB途径是使应答T细胞成为效应细胞和长寿记忆细胞的多种共刺激信号的必要共同特征。对病毒感染的有效免疫应答需要由先天免疫应答或佐剂提供的晚期共刺激信号，以使应答T细胞能够分化为效应细胞并作为长寿记忆细胞存活。本申请中提出的实验可以证明替代NFkB途径是使应答T细胞成为效应细胞和长寿记忆细胞的多种共刺激信号的必要共同特征。

Description (provided by applicant): The NFkB system is an ancient intracellular signaling pathway that coordinates the inflammatory immune response to infection in animals as diverse as worms, flies, and mammals. In lymphocytes, signals from antigen and cytokine receptors cause acute and transient activation of NFkB through the canonical pathway by triggering IkB degradation. Stimulation via a select set of cytokine receptors, including some members of the TNFR family, causes sustained activation of NFkB through the IkB-independent, NIK-dependent alternative pathway. This alternative NFkB activation pathway has recently been shown to govern formation of secondary lymphoid organs and determine the fate of newly differentiated B cells, but its function in T cells is unknown. The working hypothesis of this proposal is that sustained activation of the alternative NFkB pathway in proliferating T cells in response to late costimulatory signals induces and maintains expression of the cytokines, cytokine receptors, and anti-apoptotic proteins that are necessary for responding T cells to function as differentiated effector cells and survive as memory cells. We will test this hypothesis using mice with T cells that are deficient in the alternative NFkB pathway to determine whether the alternative pathway is necessary for T cell differentiation to effector cells and survival as long-lived memory cells in the immune response to lymphocytic choriomeningitis virus. Using retroviral transduction and Cre-inducible transgenes to express active components of the alternative pathway in T cells, we will determine whether activation of the alternative pathway is sufficient to enable generation of effector and memory T cells when costimulatory signals are limiting. The experiments proposed in this application may demonstrate that the alternative NFkB pathway is a necessary common feature of the diverse costimulatory signals that enable responding T cells to become effector cells and long-lived memory cells. An effective immune response to virus infection requires late costimulatory signals provided by the innate immune response or by adjuvants to enable the responding T cells to differentiate to effector cells and survive as long-lived memory cells. The experiments proposed in this application may demonstrate that the alternative NFkB pathway is a necessary common feature of the diverse costimulatory signals that enable responding T cells to become effector cells and long-lived memory cells.