Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes

Madhav D. Sharma, De Yan Hou, Yanjun Liu, Pandelakis A. Koni, Richard Metz, Phillip Chandler, Andrew L. Mellor, Yukai He, David H. Munn

Research output: Contribution to journalArticle

248 Citations (Scopus)

Abstract

The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by a subset of murine plasmacytoid DCs (pDCs) in tumor-draining lymph nodes (TDLNs), where it can potently activate Foxp3+ regulatory T cells (Tregs). We now show that IDO functions as a molecular switch in TDLNs, maintaining Tregs in their normal suppressive phenotype when IDO was active, but allowing inflammation-induced conversion of Tregs to a polyfunctional T-helper phenotype similar to proinflammatory T-helper-17 (TH17) cells when IDO was blocked. In vitro, conversion of Tregs to the TH17-like phenotype was driven by antigen-activated effector T cells and required interleukin-6 (IL-6) produced by activated pDCs. IDO regulated this conversion by dominantly suppressing production of IL-6 in pDCs, in a GCN2-kinase dependent fashion. In vivo, using a model of established B16 melanoma, the combination of an IDO-inhibitor drug plus antitumor vaccine caused up-regulation of IL-6 in pDCs and in situ conversion of a majority of Tregs to the TH17 phenotype, with marked enhancement of CD8+ T-cell activation and antitumor efficacy. Thus, Tregs in TDLNs can be actively reprogrammed in situ into T-helper cells, without the need for physical depletion, and IDO serves as a key regulator of this critical conversion.

Original languageEnglish (US)
Pages (from-to)6102-6111
Number of pages10
JournalBlood
Volume113
Issue number24
DOIs
StatePublished - Nov 19 2009

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Th17 Cells
Tumors
Lymph Nodes
T-cells
Neoplasms
Phenotype
Interleukin-6
T-Lymphocytes
Experimental Melanomas
Regulatory T-Lymphocytes
Helper-Inducer T-Lymphocytes
Antineoplastic Agents
Phosphotransferases
Up-Regulation
Vaccines
Chemical activation
Switches
Inflammation
Antigens

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. / Sharma, Madhav D.; Hou, De Yan; Liu, Yanjun; Koni, Pandelakis A.; Metz, Richard; Chandler, Phillip; Mellor, Andrew L.; He, Yukai; Munn, David H.

In: Blood, Vol. 113, No. 24, 19.11.2009, p. 6102-6111.

Research output: Contribution to journalArticle

Sharma, Madhav D. ; Hou, De Yan ; Liu, Yanjun ; Koni, Pandelakis A. ; Metz, Richard ; Chandler, Phillip ; Mellor, Andrew L. ; He, Yukai ; Munn, David H. / Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. In: Blood. 2009 ; Vol. 113, No. 24. pp. 6102-6111.
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