Regulation of T cell Immunity by Dendritic Cells Expressing Indoleamine 2,3- Dioxygenase (IDO)

Hdl Handle:
http://hdl.handle.net/10675.2/550561
Title:
Regulation of T cell Immunity by Dendritic Cells Expressing Indoleamine 2,3- Dioxygenase (IDO)
Authors:
Manlapat, Anna K
Abstract:
IDO-mediated tryptophan depletion inhibits T cell responses in vitro and in vivo. This work investigates the role of IDO-expressing dendritic cells (DCs) in regulating T cell responses. To determine the role of IDO-expressing DCs in the regulation o f T cell immunity, IDO-transfected DCs and IDO transgenic mice over-expressing IDO specifically in DCs were generated, and effects of IDO over-expression on T cell stimulatory functions of DCs were assessed. Results show that inhibition o f T cell proliferation in vivo requires induction of IDO expression in DCs by CTLA4-Ig rather than constitutive over-expression of IDO. In addition, we have recently shown that IDO induction leading to T cell suppression is mediated by CTLA4-Ig ligation of B7 molecules on a minor subset of DCs that express the surface marker CD 19. Interferon-a (IFNa) was rapidly produced by CD 19+ DCs after CTLA4-Ig treatment in vitro, and signaling via IFN a receptors (IFNAR) was essential for activation of the transcription factor STAT1, while IFNy signaling was not. To further understand the role of IDO expressing DCs, DCs from IDO-deficient mice were treated in vitro and in vivo with CTLA4-Ig. In addition, IDO wildtype mice were also treated in vitro with CTLA4-Ig in the presence of the pharmacological IDO inhibitor 1-methyl-tryptophan (1-MT). IFNa production in response to CTLA4-Ig was detected in IDO-WT but not in IDO-KO DCs or IDO-WT treated with 1-MT. These results show that IDO is both upstream and downstream of IFN a production following B7 ligation. This study provides a better understanding of the role of IDO in antigen-presenting cells and evaluates the tolerogenic activity of APCs.
Affiliation:
GRU Cancer Center
Issue Date:
Apr-2006
URI:
http://hdl.handle.net/10675.2/550561
Additional Links:
http://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/304955272?accountid=12365
Type:
Dissertation
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorManlapat, Anna Ken
dc.date.accessioned2015-04-24T03:37:48Zen
dc.date.available2015-04-24T03:37:48Zen
dc.date.issued2006-04en
dc.identifier.urihttp://hdl.handle.net/10675.2/550561en
dc.description.abstractIDO-mediated tryptophan depletion inhibits T cell responses in vitro and in vivo. This work investigates the role of IDO-expressing dendritic cells (DCs) in regulating T cell responses. To determine the role of IDO-expressing DCs in the regulation o f T cell immunity, IDO-transfected DCs and IDO transgenic mice over-expressing IDO specifically in DCs were generated, and effects of IDO over-expression on T cell stimulatory functions of DCs were assessed. Results show that inhibition o f T cell proliferation in vivo requires induction of IDO expression in DCs by CTLA4-Ig rather than constitutive over-expression of IDO. In addition, we have recently shown that IDO induction leading to T cell suppression is mediated by CTLA4-Ig ligation of B7 molecules on a minor subset of DCs that express the surface marker CD 19. Interferon-a (IFNa) was rapidly produced by CD 19+ DCs after CTLA4-Ig treatment in vitro, and signaling via IFN a receptors (IFNAR) was essential for activation of the transcription factor STAT1, while IFNy signaling was not. To further understand the role of IDO expressing DCs, DCs from IDO-deficient mice were treated in vitro and in vivo with CTLA4-Ig. In addition, IDO wildtype mice were also treated in vitro with CTLA4-Ig in the presence of the pharmacological IDO inhibitor 1-methyl-tryptophan (1-MT). IFNa production in response to CTLA4-Ig was detected in IDO-WT but not in IDO-KO DCs or IDO-WT treated with 1-MT. These results show that IDO is both upstream and downstream of IFN a production following B7 ligation. This study provides a better understanding of the role of IDO in antigen-presenting cells and evaluates the tolerogenic activity of APCs.en
dc.relation.urlhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/304955272?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.en
dc.subjectindoleamine 2,3 dioxygenaseen
dc.subjectdendritic cellen
dc.subjectT Cell suppressionen
dc.subjectCTLA4-Igen
dc.subjectInterferon-alphaen
dc.subjectAntigen-Presenting Cellsen
dc.titleRegulation of T cell Immunity by Dendritic Cells Expressing Indoleamine 2,3- Dioxygenase (IDO)en
dc.typeDissertationen
dc.contributor.departmentGRU Cancer Centeren
dc.description.advisorMellor, Andrewen
dc.description.committeeBollag, Wendy; Koni, Pandelakis; Ignatowics, Leszek; Smith, Sylviaen
dc.description.degreeDoctor of Philosophy (Ph.D.)en
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