Vaccines are one of the most cost effective public health tools in human history. Several experimental vaccines to fungi are being explored, but none have reached clinical trials and or are commercially available despite the increasing rates of fungal infections in healthy and immune deficient hosts. Vaccines to fungi demand a clear understanding of the mechanisms of adaptive immunity. This proposal addresses basic mechanisms of anti-fungal immunity by continuing to investigate a novel vaccine that we created against Blastomyces dermatitidis. In the last grant cycle, we began work on a genetically-engineered live attenuated vaccine. Vaccinated mice are uniformly protected against lethal pneumonia and acquire sterilizing immunity that is mediated chiefly by CD4 T-cells. Here, we propose to investigate the cellular and molecular mechanisms behind priming and long-term maintenance of vaccine induced CD4 T-cells. We have engineered the vaccine strain with model T-cell epitopes and bred the corresponding TCR transgenic mice so that we can carefully monitor and quantify pivotal stages during the induction of vaccine immunity and memory: vaccine uptake by APC, antigen delivery to the draining lymph nodes, display of peptide:MHC complexes, and priming and durability of memory CD4 T-cells at the clonal level. We hypothesize that vaccine yeast injected into the skin are captured by select dendritic cell (DC) subsets that migrate over several days to draining lymph nodes, where they move deep into the paracortex to prime naive T-cells. CD4 T-cells exert primacy in vaccine immunity in part because they out-compete CD8 T-cells for peptide: MHC complexes on the DC surface and/or modulate the detour pathway of cross-presentation. CD4 T-cells establish a dynamic pool of memory subsets - TEM and TCM - in which TCM cells ultimately confer durable memory.
Our specific aims are to: (1) Elucidate the APC that engulfs vaccine yeast and presents it to naive CD4 T-cells in the draining lymph nodes. (2) Investigate the location and kinetics of antigen presentation within the draining lymph nodes, and the ensuing priming of CD4 T-cells and establishment of durable CD4 T-cell memory. (3) Define the mechanisms behind primacy of CD4 T- cells over CD8 T-cells during the induction of vaccine immunity. Findings from our studies will delineate the fundamental mechanisms of vaccine immunity and memory to fungi. These insights will foster the rational design of vaccines against fungal pathogens and other microbial agents. ? ? ?
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