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. ? ? ?
