Grant: $222,500 - Department of Health and Human Services - May. 4, 2009
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Award Description: A goal of successful protein subunit vaccination against deadly pathogens is to establish a depot of antigens within an inflammatory context to induce protective immunity. However, the impact of antigen depots in the context of acute infection-induced inflammation has not yet been evaluated for CD4 T cell responses due to limitations of existing model systems. Our studies have demonstrated the unique ability of acute influenza virus infection to form depots of residual antigen presentation capable of recruiting new 'latecomer' naive CD4 T cells into the immune response as they are exported to the periphery from the thymus in the weeks to months following infection. The influenza-primed latecomer CD4 T cells are very efficient at persisting to memory, and constitute a large fraction of the subsequent memory population. Thus, our experimental influenza virus infection model is ideally suited to probe the potential for natural depots of residual antigen to enhance the establishment of CD4 T cell populations capable of helping mount protective anti-viral responses. Our proprosed studies are designed to utilize this unique characteristic of acute influenza infection to improve our understanding of the role of naturally retained antigen depots in the generation of protective immunity to viruses. We hypothesize that latecomer CD4 effector and memory subsets primed by residual antigen presentation exhibit more functional flexibility and will provide a broader range of protective helper functions, compared to CD4 T cell protective primed during the acute phase of influenza infection. Our readouts of immune CD4 T cell protective potential will include: 1) diversity or immunodominant influenza epitope utilization by naive CD4 T cells recruited by residual antigen depots , and 2) the establishment of effector and memory populations capable of helping protect against virus challenge. The unique aspects of the expirmental influenza infection model provide a powerful tool for determining the functional capacity of latecomer CD4 T cell subsets to help protect against viral infection, thereby generating critical information for the rational design of protein subunit depot vaccines capable of targeting conserved pathogen proteins to beneficial residual antigen depots and inducing protective anti-viral immunity. To test our hypothesis, we will address the following specific aims (1) to determine the role of residual antigen presentation in the establisment of CD4 T cell immunity, and (2) to demostrate the protective functions of early versus latecomer CD4 T cell subsets during influenza infection challenge.
Project Description: We have charaterized the immunodominant epitopes utilized by early and latercomer T cells during influenza virus infection. We have also established that the presence of residual influenza virus antigens is beneficial in the generation of a larger number of long-lived memory T cells, compared to the transition of acutely stimulated T cells in the absence of continued antigen stimulation. Now that we know the beginning experiments designed to determine whether latecomer T cells contain more functional flexibility in their cytokine polarization, compared to T cells stimulated during the acute phase of influenza virus infection.
Jobs Summary: A research assistant (Lynn Ryan) from the laboratory of a retiring investigator at the Trudeau Institute was retained and will devote 6 calendar months of her time to this project and provide critical technical help to support all aspects of the studies described. As a senior research assistant Lynn brings additional skills to the laboratory, including histology and small animal necrospy/surgery capabilities that would have been hired out to the core services at Trudeau if we had not hired her. Lynn will help with supply ordering, reagent production, animal necropsy and surgeries, tissue processing for virus titers and FACS analysis, tissue processing for RNA isolation and gene expression quantification, tissue processing for histological analysis, as well as essential experimental mouse bredding, screening, and health monitoring. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on May. 4, 2009. Help expand these official descriptions using the wiki below.