The role of TNF-alpha in dendritic cell maturation and activation of the adaptive immune response to adenovirus vectors.

摘要

Understanding the complex interactions between viruses and the host immune response has important applications in virus immunity, vaccine development and implementation of viral gene therapy vectors. The extensive study of adenoviruses as gene therapy vectors is a result of their high efficiency of gene transfer in vivo and in vitro and relative ease of production. However, in vivo administration of replication-deficient adenovirus vectors in murine models results in potent activation of the host immune system. Thus, systemic infection of mice with adenovirus vectors represents a relevant and important model to define mediators of the immune response to viruses.; TNF-α is a pleiotropic cytokine that has been shown to be involved in apoptosis, inflammation and septic shock. Currently, the mechanisms of TNF-α that influence the adaptive immune response to virus infections are not well understood. In this thesis, the role of TNF-α in activating the cellular and humoral responses to systemic adenovirus vector challenge has been studied. Investigation of T cell function in TNF-α deficient mice (TNFKO) revealed impaired virus-specific proliferation of CD8+ and CD4+ T cells isolated from the draining lymph nodes of the liver.; Critical to the initiation of adaptive immune responses to adenovirus vectors and other viruses are dendritic cells (DC). During the course of an infection, DC take up viral particles, mature and migrate to the local draining lymph node where they efficiently activate both T and B cells. Analysis of DC from the draining lymph nodes of the liver after adenovirus administration showed that DC from TNFKO mice were relatively immature compared to those from strain-matched wild type mice. To determine whether defective DC were the primary reason for the impaired T and B cell responses in TNFKO mice, we adoptively transferred primed, mature DC into TNFKO mice and challenged them with adenovirus. Giving back mature DC restored T cell responses and reconstituted anti-adenovirus antibody responses. Thus, TNF-α plays a significant role in the maturation of DC following adenovirus challenge both in vitro and in vivo, highlighting the importance of this innate cytokine in activating adaptive immunity to viral challenge.