The immunoregulatory 
enzyme indoleamine 2,3-
dioxygenase (IDO) is expressed by a subset of murine plasmacytoid DCs (pDCs) in tumor-draining LNs, where it can potently activate Foxp3 regulatory T cells (Tregs). We now show that IDO functions as a 
molecular switch in tumor-draining LNs, 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 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 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 anti-tumor vaccine caused upregulation 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 anti-tumor 
efficacy. Thus, Tregs in tumor-draining LNs can be actively re-programmed 
in vitro and 
in vivo into T-helper cells, without the need for physical depletion, and IDO serves as a key 
regulator of this critical conversion.