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dc.contributor.authorKahler, David J.
dc.date.accessioned2021-01-07T20:34:19Z
dc.date.available2021-01-07T20:34:19Z
dc.date.issued2008-10
dc.identifier.urien
dc.identifier.urihttp://hdl.handle.net/10675.2/623787
dc.description.abstractlndoleamine 2,3 Dioxygenase (IDO) is a potent immunomodulatory enzyme whose role has been described in diverse physiologic states\ including pregnancy, cancer, tissue transplants, autoimmune disease, chronic inflammation, and depression. IDO suppresses antigen specific T cell proliferation via mechanisms including tryptophan degradation and the production of toxic metabolites, and the activation of resting regulatory T cells (Tregs). IDO expression is tightly regulated in the murine spleen, as only rare dendritic cell (DC) subsets are competent to express IDO. Therefore, an accurate phenotype by which to identify IDO competent DCs in tissues is important when ascribing the role of IDO competent DCs in disease models. Here we show that IDO competent CD19+ pDCs (CD19+ pDCs) express high levels of costimulatory receptors (CD80 I CD86) under homeostatic conditions indicating a mature or activated phenotype and uniquely express the Class I MHC-like molecule CD1d, and the chemokine receptor CCR6. IDO competent pDCs do not share the same lineage as other murine splenic DCs as they were the only DC subset to express Pax5, and were present in reduced numbers in murine models of 8 cell development indicating that they develop from 8 cell precursors. Distinct signaling requirements regulate IDO induction in IDO competent pDCs as MyD88 was required for IDO induction and function in inflamed skin draining lymph nodes following phorbol myristate acetate application but not for I DO transcript expression or STAT1 or STAT2 protein phosphorylation following treatment with recombinant cytokines. CD19+ pDCs from wr mice but not mice genetically deficient for the IDO1 gene formed stress granules (SG) following treatment with IFNy, which were not prevented by inhibitors of IDO activity indicating that SG formation was not IDO dependent. We hypothesize that IDO competent murine splenic pDCs uniquely expressing CD19 are phenotypically and functionally distinct from other splenic DC subsets and respond to inflammatory signals by expressing IDO. We further hypothesize that activated IDO causes distinct yet undefined biochemical changes within IDO competent pDCs following induction most probably by activating the integrated stress response and the eif2a kinases GCN2, PKR, and PERK.en_US
dc.language.isoen_USen_US
dc.publisherAugusta Universityen_US
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en_US
dc.subjectID0en_US
dc.subjectCD19+en_US
dc.subjectTryptophanen_US
dc.titleMurine CD19+ plasmacytoid dendritic cells expressing indolamine 2,3 dioxygenaseen_US
dc.typeDissertationen_US
dc.contributor.departmentMedical College of Georgiaen_US
dc.description.advisorN/A, N/A
dc.description.committeeN/A, N/A
dc.description.degreeDoctor of Philosophyen_US
dc.embargoen
refterms.dateFOA2021-01-07T20:34:19Z


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