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

Abstract

IntroductionRegulatory T cells (Tregs) represent a critical barrier to immunotherapy of tumors. Established tumors suppress immune responses against their own antigens, and Tregs are emerging as a key mechanism contributing to this state of functional unresponsiveness. 1 In murine models, host Tregs become activated within days of tumor implantation. 2 Once activated, Tregs are difficult to eliminate and serve to potently and dominantly inhibit otherwise effective immune responses against the tumor. 3 We have shown that Foxp3 ϩ Tregs in the draining lymph nodes of mouse tumors become highly activated by exposure to the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). 4,5 In tumor-draining lymph nodes (TDLNs), IDO is expressed by a specific subset of IDO-competent plasmacytoid dendritic cells (DCs). 6 The combination of these IDO-expressing pDCs and IDO-activated Tregs renders the local milieu in the TDLNs profoundly inhibitory for T-cell activation. 7 Tregs can be suppressive, but this is not a fixed and immutable attribute. Resting Tregs are not spontaneously suppressive, and require an activation step before they become functionally inhibitory. 8 Conversely, the suppressive phenotype of Tregs is plastic. When Foxp3 is artificially ablated in mature Tregs, the suppressor phenotype is converted to a proinflammatory, T helper-like phenotype that can participate in autoimmunity. 9 Likewise, Tregs exposed to certain inflammatory signals (eg, from activated DCs or TLR ligands) can lose their suppressor activity 10 and may alter their phenotype (be "reprogrammed") to resemble proinflammatory effector cells. [11][12][13] Thus, at least in these experimental models, Tregs show a significant degree of phenotypic plasticity and are susceptible to both activation and deactivation (reprogramming) by signals from their local microenvironment.However, it is not known whether this apparent plasticity of Tregs is of biologic relevance for tumor immunology. In the current study, we test the hypothesis that, under conditions of antigendriven T-cell response to tumors, IDO functions as a critical molecular "switch" in TDLNs, regulating the phenotype and functional activity of Tregs. We show that, when IDO is active, Tregs are maintained in their normal potently suppressive state; but when IDO is blocked, Tregs undergo an inflammation-induced, interleukin-6 (IL-6)-dependent conversion into a nonsuppressive, proinflammatory phenotype similar to T-helper-17 (TH17) cells. These findings position IDO as a previously unsuspected key molecular regulator of Treg phenotype and function in TDLNs. Methods Reagents, cell lines, and mouse strainsA complete list of reagents, 1-methyl-D-tryptophan (1MT) preparation, tumor cell lines, and all transgenic and knockout mouse strains is given in supplemental materials (available on the Blood website; see the Supplemental Materials link at the top of the online article). Animal studies were approved by the Institutional Animal Care and Use Committee of the Medical College of Georgia. Detail...

CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor

“…It has been proposed that IL-17-mediated inflammation is tumor-promoting during the initial phase of tumor growth, whereas Th17 cells are anti-tumorigenic in established tumors (Wilke et al, 2011). The biological relevance of FoxP3 þ IL-17 þ converted Treg cells or Th17 matured CD4 þ cells is supported by studies with tumor models, where these cells can induce anti-tumor CD8 þ T-cell responses (Martin-Orozco et al, 2009;Sharma et al, 2009Sharma et al, , 2010. In the absence of CD200 signaling, we demonstrate that FoxP3 þ IL-17 þ are more frequent in skin-draining LNs.…”

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation

“…58 Furthermore, treatment with adoptive T-cell transfer can result in synergistic anti-neoplastic effects owing to the increased immunogenicity of cancer cells. 59 Yet, for all these antitumor effects, there appears to be a balance between anti-and pro-tumor effects by both CD4 þ and CD8 þ T cells, [60][61][62] and regulatory T cells can migrate into the microenvironment and suppress antitumor responses in human ovarian carcinoma. 63 Considering the variable effects of this multitude of stromal cell and immune response interactions, the mechanism by which p53 deficiency in MSCs affects T-cell function in tumors warrants further exploration.…”

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

“…Engagement of several receptors, including CD80/CD86, or TLR9 59 , participates in active IDO induction. Amino acid withdrawal resulting from IDO enzymatic activity, stimulates the GCN2 kinase in PDC and then prevents IL-6 secretion by PDC 9 . Moreover, IDO exerts a regulatory function independently of its catabolic activity by participating in TGF-β-signaling pathway 60 .…”

“…Finally, concerning amino acid metabolism, PDC are able to sense amino acid deficiency through their expression of GCN2 (general control nonderepressible 2) serine/threonine kinase. Indeed, the suppression of interleukin (IL)-6 production in PDC by indoleamine 2,3-dioxygenase (IDO) involves GCN2 kinase 9 (see section 2.3).…”