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

• Published in: Blood 2009-06, Vol.113 (24), p.6102-6111
• Main Authors: Sharma, Madhav D., Hou, De-Yan, Liu, Yanjun, Koni, Pandelakis A., Metz, Richard, Chandler, Phillip, Mellor, Andrew L., He, Yukai, Munn, David H.
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Biological and medical sciences; Blotting, Western; Cancer Vaccines - therapeutic use; Chickens; Dendritic Cells - immunology; Forkhead Transcription Factors - metabolism; Hematologic and hematopoietic diseases; Immunobiology; Immunophenotyping; Indoleamine-Pyrrole 2,3,-Dioxygenase - physiology; Interleukin-17 - metabolism; Interleukin-6 - metabolism; Lymph Nodes - enzymology; Lymph Nodes - immunology; Lymphocyte Activation; Medical sciences; Melanoma, Experimental - enzymology; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Mice; Mice, Knockout; Mice, Transgenic; Ovalbumin - physiology; Receptors, Antigen, T-Cell - physiology; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - pathology; T-Lymphocytes, Regulatory - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-12-195354

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.