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

描述(申请人提供)：NFkB系统是一种古老的细胞内信号通路，协调各种动物如蠕虫、苍蝇和哺乳动物对感染的炎性免疫反应。在淋巴细胞中，来自抗原和细胞因子受体的信号通过典型的途径引起NFkB的急性和瞬时激活，从而引发IKB降解。通过选择一组细胞因子受体，包括TNFR家族的一些成员的刺激，导致NFkB的持续激活，通过IkB不依赖的，Nik依赖的替代途径。最近研究表明，这种可供选择的NFkB激活途径控制次级淋巴器官的形成，并决定新分化的B细胞的命运，但它在T细胞中的功能尚不清楚。这一建议的工作假设是，对晚期共刺激信号的反应，在增殖的T细胞中持续激活NFkB途径，诱导并维持细胞因子、细胞因子受体和抗凋亡蛋白的表达，这些是反应T细胞发挥分化效应细胞功能和作为记忆细胞生存所必需的。我们将使用T细胞缺乏替代NFkB途径的小鼠来验证这一假设，以确定替代途径是否对于T细胞分化为效应细胞以及在淋巴细胞性脉络膜脑膜炎病毒的免疫反应中作为长期记忆细胞存活是必要的。使用逆转录病毒转导和Cre诱导的转基因在T细胞中表达替代途径的活性成分，我们将确定当共刺激信号有限时，替代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能证明，替代NFkB途径是各种共刺激信号的必要共同特征，使反应性T细胞成为效应细胞和长寿命记忆细胞。对病毒感染的有效免疫反应需要由先天免疫反应或佐剂提供的晚期共刺激信号，使反应的T细胞分化为效应细胞，并作为长期记忆细胞存活。本申请中提出的实验可能证明，替代NFkB途径是各种共刺激信号的必要共同特征，使反应性T细胞成为效应细胞和长寿命记忆细胞。

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.