Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells

David J. Chung, Marco Rossi, Emanuela Romano, Jennifer Ghith, Jianda Yuan, David H Munn, James W. Young

Research output: Contribution to journalArticle

163 Citations (Scopus)

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+CD25 brightFoxp3+CD127neg Tregs. Treg expansion requires moDC contact, CD80/CD86 ligation, and endogenous interleukin-2. Cytofluorographically sorted CD4+ CD25brightFoxp3 + 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+CD25 brightFoxp3+ 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.

Original languageEnglish (US)
Pages (from-to)555-563
Number of pages9
JournalBlood
Volume114
Issue number3
DOIs
StatePublished - Nov 19 2009

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Indoleamine-Pyrrole 2,3,-Dioxygenase
T-cells
Regulatory T-Lymphocytes
Dendritic Cells
Monocytes
T-Lymphocytes
Immunotherapy
Wilms Tumor
Transforming Growth Factors
Cytotoxic T-Lymphocytes
Neoplasm Antigens
Interleukin-2
Ligation
Cell proliferation
Up-Regulation
Cell Proliferation
Cytokines
Enzymes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. / Chung, David J.; Rossi, Marco; Romano, Emanuela; Ghith, Jennifer; Yuan, Jianda; Munn, David H; Young, James W.

In: Blood, Vol. 114, No. 3, 19.11.2009, p. 555-563.

Research output: Contribution to journalArticle

Chung, David J. ; Rossi, Marco ; Romano, Emanuela ; Ghith, Jennifer ; Yuan, Jianda ; Munn, David H ; Young, James W. / Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. In: Blood. 2009 ; Vol. 114, No. 3. pp. 555-563.
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