Murine CD19+ Plasmacytoid Dendritic Cells Expressing Indoleamine 2,3 Dioxygenase

Hdl Handle:
http://hdl.handle.net/10675.2/317265
Title:
Murine CD19+ Plasmacytoid Dendritic Cells Expressing Indoleamine 2,3 Dioxygenase
Authors:
Kahler, David J.
Abstract:
Indoleamine 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 / 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 B cell development indicating that they develop from B 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 IDO transcript expression or STAT1 or STAT2 protein phosphorylation following treatment with recombinant cytokines. CD19+ pDCs from WT mice but not mice genetically deficient for the IDO1 gene formed stress granules (SG) following treatment with IFNγ, 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.
Affiliation:
Department of Cellular Biology and Anatomy
Issue Date:
Oct-2008
URI:
http://hdl.handle.net/10675.2/317265
Additional Links:
http://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/304403610?accountid=12365
Type:
Dissertation
Language:
en_US
Appears in Collections:
Theses and Dissertations; Department of Cellular Biology and Anatomy Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorKahler, David J.en
dc.date.accessioned2014-05-21T19:54:08Z-
dc.date.available2014-05-21T19:54:08Z-
dc.date.issued2008-10-
dc.identifier.urihttp://hdl.handle.net/10675.2/317265-
dc.description.abstractIndoleamine 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 / 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 B cell development indicating that they develop from B 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 IDO transcript expression or STAT1 or STAT2 protein phosphorylation following treatment with recombinant cytokines. CD19+ pDCs from WT mice but not mice genetically deficient for the IDO1 gene formed stress granules (SG) following treatment with IFNγ, 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
dc.language.isoen_USen
dc.relation.urlhttp://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/304403610?accountid=12365en
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.-
dc.subjectIDOen
dc.subjectCD19+ pDCen
dc.subjectPax5en
dc.subjectMyD88en
dc.subjectPMAen
dc.subjectType I IFNen
dc.subjectType II IFNen
dc.subjectSTAT1en
dc.subjectSTAT2en
dc.subject1DMTen
dc.subjectTryptophanen
dc.subjectStress Granulesen
dc.subjectG3BPen
dc.titleMurine CD19+ Plasmacytoid Dendritic Cells Expressing Indoleamine 2,3 Dioxygenaseen
dc.typeDissertationen
dc.contributor.departmentDepartment of Cellular Biology and Anatomyen
dc.description.advisorMellor, Andrew L.-
dc.description.committeeMunn, David; Thompson, Stuart; Caldwell, Ruth; He, Yukai.-
dc.description.degreeDoctor of Philosophy (Ph.D.)-
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