The mucosal immune system is constantly exposed to a wide range of commensal and potentially pathogenic microbial species. This chronic exposure to inflammatory mediators and nonpathogenic organisms makes generation of an appropriate immune response critical in maintaining a balance between elimination of harmful pathogens and regulating responses to nonpathogenic organisms. While Listeria monocytogenes (LM) (a category B Biodefense priority pathogen) is one of the most widely utilized pathogens for examining T cell immune responses, little is known about induction of the mucosal CD8 T cell response after oral infection. The overall hypothesis to be tested is that effector CD8 T cell subsets are differentially regulated by mucosal environmental cues to promote rapid local protection. We will address this hypothesis using a new oral infection model that more closely mimics the human infection.
The specific aims of the project are:
Aim 1 : To define the anatomical events leading to generation of protective mucosal CD8 T cell memory.
Aim 2 : To understand the dynamics of CD8 T cell priming in response to oral bacterial infection.
Aim 3 : To define the mechanisms regulating development of protective mucosal CD8 memory T cells. The studies proposed will examine the eariiest events of CD8 T cell differentiation through memory T cell homeostasis and recall to secondary challenge. Examining the induction of effector T cells and the maintenance and recall of memory T cells to a bona fide gut pathogen that closely mimics human infection is critical for a better understanding of CD8 T cell immunity in the intestinal mucosa. The knowledge gained from this proposal has broad application potential ranging from understanding the immune response to intestinal pathogens to mucosal vaccine designs.
This project will define the parameters controlling the immune response to an intestinal bacterial infection transmitted through ingestion of the pathogen. The mouse model used recapitulates the human infection and therefore has direct relevance to understanding mucosal immunity and vaccination.
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