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Delineating The Roles of IL-12 and IL-23 Produced by Dendritic Cells in Eliciting CD8+ T Cell Resonses Against Listeria Monocytogenes

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abstract
Interleukin-12 family members are important links between innate and adaptive immunity. IL-12 drives Th1 responses by augmenting IFN-γ production – key for clearance of intracellular pathogens. IL-23 promotes the development of IL-17 producing CD4+ T cells that participate in the control of extracellular pathogens and the induction of autoimmunity. These cytokines modulate T cell activation during primary responses; however, it is still unclear if priming in the presence of these cytokines affects secondary T cells responses. We sought to determine the individual roles of IL-12 and IL-23 in naïve CD8+ T cell activation by determining their ability to influence IFN-γ production and cellular interactions during priming by Listeria monocytogenes (Lm) infected dendritic cells (DC), and whether IL-12 or IL-23 enhanced secondary T cell responses against Lm. During the primary immune response, we found that IL-12, not IL-23, was the major cytokine that promoted CD8+ T cell IFN-γ production in vitro and had a significant impact during the first two days of priming. We observed that IL-12 promoted longer duration conjugation events between CD8+ T cells and DC, a result of the increased production of the chemokines CCL1 and CCL17 by WT, but not IL-12 deficient DC. Neutralization of both chemokines resulted in reduced IFN-γ production, demonstrating their importance in priming naïve CD8+ T cells. These chemokines did not influence CD4+ T cell IFN-γ production. To address the role of these cytokines in eliciting anti-listerial secondary responses in vivo, we used a DC based vaccination strategy. We found that IL-12 and IL-23 augmented the number of memory cells that were generated from vaccination, which mediated faster clearance of Lm when mice were challenged with an intermediate dose of Lm and complete protection when mice were infected with high doses of Lm. Our study demonstrates that IL-12 augments naïve CD8+ T cell primary responses by facilitating chemokine production, promoting more stable cognate interactions during priming. We determined that IL-12 and IL-23 enhances secondary responses by increasing the size of the memory CD8+ T cell pool. This knowledge should be applied to the development of future vaccines and therapeutics against intracellular pathogens and tumors. xiii
subject
Dendritic Cells
T Cells
Listeria Monocytogenes
contributor
Henry, Curtis (author)
Mark Willingham (committee chair)
Martha Alexander-Miller (committee member)
Jason Grayson (committee member)
David Ornelles (committee member)
William Swords (committee member)
date
2009-04-01T15:31:34Z (accessioned)
2010-06-18T18:56:59Z (accessioned)
2009-04-01T15:31:34Z (available)
2010-06-18T18:56:59Z (available)
2009-04-01T15:31:34Z (issued)
degree
Microbiology & Immunology (discipline)
identifier
http://hdl.handle.net/10339/14660 (uri)
language
en_US (iso)
publisher
Wake Forest University
rights
Release the entire work immediately for access worldwide. (accessRights)
title
Delineating The Roles of IL-12 and IL-23 Produced by Dendritic Cells in Eliciting CD8+ T Cell Resonses Against Listeria Monocytogenes
type
Dissertation
Thesis

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