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Pathogenic and Protective T Cells in Toxoplasmosis


A successful cellular immune response to Toxoplasma gondii and many other intracellular pathogens involves a delicate balance between the actions of IL-12, a proinflammatory innate cytokine triggered by the parasite and IL-10, a regulatory cytokine produced by adaptive T cells to prevent immunopathology. <P> The overall goal of this proposal is to explore how IL-12 controls the generation and persistence of parasitereactiveCD8 effector and memory cells required for protective immunity and how IL-10acts in a novel autocrine fashion to avert tissue damage. <P> Using a new mouse model with T-cell lineage specific interference in IL-10 signaling, we have obtained evidence that IL-10 activation of a T-cell intrinsic anti-inflammatory response is required to prevent morbidity and mortality during T. gondii infection. We will use this transgenic and other knockout mouse models to elucidate the kinetics, regulation and functional consequences of IL-10 responsiveness during the Th1 response to T. gondii and explore a novel mechanism for how IL-10 cell-autonomously restrains Th1 cytokine responses. <P> We have recently described four subpopulations of CD8 cells induced by immunization with the cps-vaccine strain of T. gondii and have published evidence that IL-12 is critically required for the generation of effector CD8 T cells expressing IFN?, granzyme B andKLRG1. <P> In collaboration with Dr. Hidde Ploegh s laboratory at MIT, we have identified the first Kb-restricted CTL epitope from T. gondii and our collaborators have also developed a cloned mouse line bearing monoclonal naive CD8 T cells reactive to this Kb restricted T. gondii antigen. <P> Using these new mouse and immunological reagents, we will elucidate the cytokine requirements, lineage relationships and functional significance of the heterogenous CD8 T cell subsets induced by T. gondii vaccination and infection. We will critically assess the costs and benefits of IL-12 signaling on the immediate and recallCD8 protective response to re-infection.

More information

For additional information, including history, sub-projects, results and publications, if available, visit the <a href="; target="blank">Project Information web page</a> at the National Institutes of Health Research Portfolio Online Reporting Tool (RePORTER) database.

Yap, George
University of Medicine & Dentistry of New Jersey
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