Abstract
Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in many settings including cancer. In recent years, we have described spontaneous CD8+ as well as CD4+ T-cell reactivity against IDO in the tumor microenvironment of different cancer patients as well as in the peripheral blood of both cancer patients and to a lesser extent in healthy donors. We have demonstrated that IDO-reactive CD8+ T cells were peptide-specific, cytotoxic effector cells, which are able to recognize and kill IDO-expressing cells including tumor cells as well as dendritic cells. Consequently, IDO may serve as a widely applicable target for immunotherapeutic strategies with a completely different function as well as expression pattern compared to previously described antigens. IDO constitutes a significant counter-regulatory mechanism induced by pro-inflammatory signals, and IDO-based immunotherapy may consequently be synergistic with additional immunotherapy. In this regard, we have shown that the presence of IDO-specific T cells boosted immunity against CMV and tumor antigens by eliminating IDO+ suppressive cells and changing the regulatory microenvironment. The current review summarizes current knowledge of IDO as a T-cell antigen, reports the initial results that are suggesting a general function of IDO-specific T cells in immunoregulation, and discusses future opportunities.
Highlights
Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in many settings including cancer
When IDO? dendritic cells (DC) are injected in vivo, they create suppression and anergy in antigen-specific T cells in the LN draining the injection site [3, 25]
GC non-derepressing 2 kinase (GCN2) responds to elevations in uncharged tRNA, as would occur if the T cell were deprived of tryptophan [24]
Summary
The immune system is delicately balanced between immunity and tolerance to protect the host from pathogens while minimizing local damage to tissues. IDO expression can suppress effector T cells directly by degradation of the essential amino acid tryptophan. GCN2 responds to elevations in uncharged tRNA, as would occur if the T cell were deprived of tryptophan [24] Another effect of IDO is mediated through enhancement of local Treg-mediated immune suppression. Constitutive IDO expression in DC provides T cells with regulatory properties that block T-cell responses to antigenic stimulation [24]. IDO does suppress effector T cells directly and influence Tregs bystander suppressor activity [2, 32, 39]. IDO suppression of pro-inflammatory processes may dominantly block effector T-cell responses to antigens encountered. Absence of IDO activity may not elicit local Treg suppression even when strong pro-inflammatory stimuli are present. It was recently shown that IDO has a nonenzymic function that contributes to TGF-b driven tolerance in non-inflammatory contexts [29]
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