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通路，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引发IkB降解的典型途径引起NFkB的急性和短暂激活。通过一系列细胞因子受体（包括TNFR家族的一些成员）的刺激，通过ikb独立、nik依赖的替代途径导致NFkB的持续激活。这种可选择的NFkB激活途径最近被证明控制次级淋巴器官的形成并决定新分化B细胞的命运，但其在T细胞中的功能尚不清楚。该建议的工作假设是，在增殖的T细胞中，为了响应晚期共刺激信号，NFkB通路的持续激活可诱导并维持细胞因子、细胞因子受体和抗凋亡蛋白的表达，这些是应答T细胞作为分化效应细胞和作为记忆细胞存活所必需的。我们将使用缺乏NFkB替代通路的T细胞小鼠来验证这一假设，以确定在淋巴细胞性脉络丛脑膜炎病毒的免疫反应中，替代通路是否对T细胞分化为效应细胞和作为长期记忆细胞存活是必要的。利用逆转录病毒转导和可诱导基因在T细胞中表达可选通路的活性成分，我们将确定当共刺激信号受限时，可选通路的激活是否足以使效应T细胞和记忆T细胞产生。本应用中提出的实验可能表明，NFkB通路是多种共刺激信号的必要共同特征，这些信号使应答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应答需要先天免疫应答或佐剂提供的晚期共刺激信号，以使应答的T细胞分化为效应细胞并作为长寿命记忆细胞存活。本应用中提出的实验可能表明，NFkB通路是多种共刺激信号的必要共同特征，这些信号使应答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.