Vaccine efficacy is strongly associated to induction of T and B cell memory. Molecular interactions that lead Dendritic cells (DCs) to promote the differentiation and persistence of memory are yet to be identified specially at mucosal sites, the port of entry of several viruses including flu. Our hypothesis is that several new viral vaccines including vaccines to flu are not efficient in part because they do not induce broad repertoires of memory B and T cells at mucosal sites. One way to improve on the qualitative and quantitative features of immunological memory is to elicit specific signaling pathways in DCs through the targeting of cell surface molecules on DCs. In this consortium our objective will be to identify DC specific fusion proteins best capable of inducing at mucosal sites B and T cell memory cells that are diverse and polyfunctional, persistent and multipotent. We will define properties of memory B and T cells in flu infected individuals and in individuals that have been immunized with current licensed vaccines (aim 1);polychromatic flow cytometry, TCP repertoire diversity assays, functional assays and systems biology approaches will allow us to define the diversity, functionality, persistence, resistance to apoptosis and self renewal of memory CD4 and CDS T cells as well as B cells. In particular we will target the FOXO3A and stat 5A pathways which we have shown are essential for the development of a persistent memory response in B and T cells.
In aim 2 we will work together with other members of the consortium to assess and compare using in the same set of assays as in aim 1 the capacity of DC fusion proteins to elicit strong B and T cell memory starting with T and B cells resident of mucosal and systemic (PBMCs) sites. We will monitor the capacity of these DC fusion proteins to induce the expression of negative regulators of the immune response including PDL-1, 11-10 , INDO and Adora. This strategy will help identify DC fusion proteins or combinations thereof that can be assessed for their capacity to induce in vivo in primates and Hu-mice persistent memory B and T cells (aim 3). Again the same battery of assays will allow us to monitor different qualitative and quantitative features of the immune response and will allow us to select the best candidate to move to human trials.
All in this consortium with its encompassing approach will allow us to identify molecular pathways involved in induction of long lasting T and B cell memory. The new approaches which we will have developed and validated using several experimental strategies will prove important milestones in developing vaccines that are highly protective.
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