Regulation of T cell immunity by dendritic cells expressing indoleamine 2,3-dioxygenase | Posted on:2007-02-25 | Degree:Ph.D | Type:Dissertation | University:Medical College of Georgia | Candidate:Manlapat, Anna Katrina | Full Text:PDF | GTID:1444390005964026 | Subject:Health Sciences | Abstract/Summary: | | 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 of 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 of 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 CD19. Interferon-alpha (IFNalpha) was rapidly produced by CD19+ DCs after CTLA4-Ig treatment in vitro, and signaling via IFNalpha receptors (IFNAR) was essential for activation of the transcription factor STAT1, while IFNgamma 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). IFNalpha 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 IFNalpha 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. | Keywords/Search Tags: | Cell, IDO, Role, Dcs, Vitro | | Related items |
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