• The effects of transforming growth factor - beta on macromolecular synthesis by human gingival and periodontal ligament fibroblasts

      Manlapat, Anna Katrina; Department of Oral Biology (2006-04)
      !DO-mediated tryptophan depletion inhibits T cell responses in vitro and in vivo. This work investigates the role of !DO-expressing dendritic cells (DCs) in regulating T c_ell responses. To determine the role of !DO-expressing DCs in the regulation of T cell immup.ity, 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 CD 19. Interferon-a (IFNa) was rapidly produced by CD19+ DCs after CTLA4-Ig treatment in vitro, _and signaling via IFN a receptors (IFNAR) was esse:μtial for activation of the transcription factor STATl, while IFNy signaling was not. To further understand the role of IDOexpressing DCs, DCs from !DO-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 ~ownstream of IFNa 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.