IDO Activates Regulatory T Cells and Blocks Their Conversion into Th17-Like T Cells

Abstract

TLR ligands are effective vaccine adjuvants because they stimulate robust pro-inflammatory and immune effector responses, and abrogate suppression mediated by regulatory T cells (Tregs)2. Paradoxically, systemic administration of high doses of CpG oligonucleotides (CpGs) that bind to TLR9 ligands stimulated Tregs in mouse spleen to acquire potent suppressor activity dependent on interactions between PD-1 and its ligands. This response to CpG treatment manifested in a few hours, and was mediated by a rare population of plasmacytoid dendritic cells (CD19+ pDCs) induced to express the immunosuppressive enzyme IDO after TLR9 ligation. When IDO was blocked CpG treatment did not activate Tregs, but instead stimulated pDCs to uniformly express the pro-inflammatory cytokine IL-6, which in turn re-programmed Foxp3-lineage Tregs to express IL-17. Thus, CpG-induced IDO activity in pDCs acted as a pivotal molecular switch that induced Tregs to acquire a stable suppressor phenotype, while simultaneously blocking CpG-induced IL-6 expression required to re-program Tregs to become TH17-like effector T cells. These findings support the hypothesis that IDO dominantly controls the functional status of Tregs in response to inflammatory stimuli in physiologic settings.

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

“…Finally, the upregulation of IDO in melanoma lymph node metastases has been associated with increased amounts of TITregs [49]. Accordingly, IDO expression by antigen-presenting cells (APCs) has been reported to directly activate Tregs and promote their proliferation [50,51].…”

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

“…It is very likely that one or more subsets of Tregs are involved that suppress T H 2 effector cells because IDO is, by multiple pathways, involved in the generation and/or activation of Tregs (48,49). It is conceivable that IDO induction during SIT generates regulatory ILT3 + ILT4 + DCs by trp deprivation, which in turn induces Tregs from CD4 + CD25 -effector T cells.…”

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

“…Tolerance to exogenous antigens can be conferred by transfer of Treg cells from tolerized animals into naive recipients (Unger et al, 2003b). However, in inflammatory conditions Treg cells can change their phenotype and start to produce interleukin (IL)-17, mimicking Th17 cells (Koenen et al, 2008;Zhou et al, 2008;Baban et al, 2009;Chung et al, 2009;Murphy and Stockinger, 2010). Th17 cells specifically express the transcription factor RORg and are mostly known for their instrumental role in the development of autoimmune diseases (Fouser et al, 2008).…”