Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and small children. RSV infection in mice is characterized by significant immunopathology which is mediated by CD8+ cytotoxic T lymphocytes (CTL). Past studies have suggested that CD8+ T cells with different functional properties and characteristics can be elicited following infection or immunization, and may have differential effects on viral clearance and RSV-associated illness. These differences in clonotype, functional avidity, and other intrinsic parameters of the CD8+ T cell response may dictate the epitope hierarchy established following infection. In dissecting the CD8+ T cell responses in mice, we have discovered differences between neonatal and adult CD8+ T cell responses elicited during RSV infection and have now defined the dynamics of lung-migratory dendritic cell populations in the lung and lung-draining lymph nodes of RSV-infected mice during early life as compared to adulthood. These dendritic cells were found to induce T cell responses in an age-dependent manner, and we have implicated lower costimulatory molecule expression by neonatal dendritic cells as one mechanism for this difference. We have recently developed a murine adult bone-marrow and fetal liver dendritic cell culture model to further characterize the phenotype and function of important dendritic cell subset. We continue to collaborate with a group at Leiden Institute of Chemistry to investigate mechanisms of controlling CD8+ T cell recognition using chemical methods. We have now begun to assess how the composition of vaccines, e.g. whether they are soluble protein or displayed on nanoparticles effects trafficking to and within the draining lymph nodes. Additionally, we have examined the contribution of CD4 T cells and CD8 T cells to immunopathology and viral clearance. CD4 T cells can influence and regulate the function of other immune effectors including CD8 T cells. In addition to the potential role of Th2 CD4 T cells in RSV pathogenesis as mentioned above, T regulatory cells have properties that suggest they may be important in RSV immunity and pathogenesis. We are currently evaluating the recruitment of regulatory T cells during primary and secondary infections. Finally, we have demonstrated that intranasal vaccination with murine cytomegalovirus vectors that persistently expressing RSV antigens promotes tissue-resident memory CD8+ T cells which protect against RSV challenge.
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