Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells Journal Article
| Authors: | Chung, D. J.; Rossi, M.; Romano, E.; Ghith, J.; Yuan, J.; Munn, D. H.; Young, J. W. |
| Article Title: | Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells |
| Abstract: | A comprehensive understanding of the complex, autologous cellular interactions and regulatory mechanisms that occur during normal dendritic cell (DC)-stimulated immune responses is critical to optimizing DC-based immunotherapy. We have found that mature, immunogenic human monocyte-derived DCs (moDCs) up-regulate the immune-inhibitory enzyme, indoleamine 2,3-dioxygenase (IDO). Under stringent autologous culture conditions without exogenous cytokines, mature moDCs expand regulatory T cells (Tregs) by an IDO-dependent mechanism. The priming of resting T cells with autologous, IDO-expressing, mature moDCs results in up to 10-fold expansion of CD4<sup>+</sup>CD25 <sup>bright</sup>Foxp3<sup>+</sup>CD127<sup>neg</sup> Tregs. Treg expansion requires moDC contact, CD80/CD86 ligation, and endogenous interleukin-2. Cytofluorographically sorted CD4<sup>+</sup> CD25<sup>bright</sup>Foxp3 <sup>+</sup> Tregs inhibit as much as 80% to 90% of DC-stimulated autologous and allogeneic T-cell proliferation, in a dose-dependent manner at Treg: T-cell ratios of 1:1, 1:5, and as low as 1:25. CD4<sup>+</sup>CD25 <sup>bright</sup>Foxp3<sup>+</sup> Tregs also suppress the generation of cytotoxic T lymphocytes specific for the Wilms tumor antigen 1, resulting in more than an 80% decrease in specific target cell lysis. Suppression by Tregs is both contact-dependent and transforming growth factor-β-mediated. Although mature moDCs can generate Tregs by this IDO-dependent mechanism to limit otherwise unrestrained immune responses, inhibition of this counter-regulatory pathway should also prove useful in sustaining responses stimulated by DC-based immunotherapy. © 2009 by The American Society of Hematology. |
| Keywords: | controlled study; protein expression; human cell; genetics; transcription factor foxp3; cell proliferation; t lymphocyte; t-lymphocytes; cytology; cells, cultured; dendritic cell; enzymology; cd4+ cd25+ t lymphocyte; regulatory t lymphocyte; antigen presentation; immunology; dendritic cells; immunotherapy; cell culture; t-lymphocytes, regulatory; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; cytolysis; upregulation; indoleamine 2,3 dioxygenase; protein folding; monocyte; indoleamine-pyrrole 2,3,-dioxygenase; monocytes; up-regulation |
| Journal Title: | Blood |
| Volume: | 114 |
| Issue: | 3 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2009-07-16 |
| Start Page: | 555 |
| End Page: | 563 |
| Language: | English |
| DOI: | 10.1182/blood-2008-11-191197 |
| PUBMED: | 19465693 |
| PROVIDER: | scopus |
| PMCID: | PMC2713474 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 16" - "Export Date: 30 November 2010" - "CODEN: BLOOA" - "Source: Scopus" |
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