Interferon-γ–triggered indoleamine 2,3-dioxygenase competence in human monocyte-derived dendritic cells induces regulatory activity in allogeneic T cells

Abstract

The role of the tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) in down-regulating human alloresponses has recently been controversially debated. We here demonstrate that human monocyte-derived dendritic cells (mDCs) can be endowed with sustained IDO competence in vitro by 48-hour activation with lipopolysaccharide (LPS) and interferon-gamma (IFN-␥). IFN-␥ also amplified proinflammatory cytokine secretion during activation. Yet, on reculture after activation cytokine production ceased, whereas IDO enzymatic activity IntroductionIndoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in tryptophan catabolism, has attracted attention for its proposed role in tolerance induction. 1,2 IDO, when expressed in antigen presenting cells (APCs), such as dendritic cells (DCs), establishes a microenvironment that at the DC/T-cell interface is depleted of tryptophan and enriched with tryptophan metabolites. Because of this alteration of the intercellular microenvironment, IDO activity has been suggested to impair T-cell responses. 3,4 The mechanisms of IDO-mediated inhibition include that T cells stimulated under tryptophan-depleted conditions are impaired to undergo full cell cycle progression 3,5 and are susceptible to apoptotic cell death. 6,7 Furthermore, it has been reported that IDO-expressing DCs can expand naturally occurring regulatory T cells. 8 In a murine model Fallarino et al 9 have shown that IDO activity supported the generation of adaptive regulatory T cells. Likewise, human IDOexpressing tumor cells have been reported to induce CD4 ϩ CD25 ϩ regulatory T cells. 10 Most recently, the previously recognized immunoregulatory activity of human plasmacytoid DCs has been related to IDO activity. 11 Thus, IDO-mediated down-regulation of T-cell responses has been suggested to be involved in a multitude of immunoregulatory processes, for example, pregnancy, 12 tumor growth, 13 and the induction of tolerance in transplantation (reviewed in Hainz et al 14 ).IDO expression is not a constitutive feature of human DCs in homeostatic immunologic conditions but requires induction. Among the multiple mediators of IDO induction (reviewed in Puccetti 15 ), interferon-␥ (IFN-␥) plays a prominent role. 16 IFN-␥ has generally been considered a prototypic proinflammatory cytokine (reviewed in Schoenborn and Wilson 17 ); compelling evidence, however, supports the ability of IFN-␥ to promote anti-inflammatory responses. [18][19][20] The ability of IFN-␥ to induce IDO has been suggested as a critical factor linked to this anti-inflammatory activity. 21,22 In our previous studies addressing possible mechanisms of the immunodeficient state after hematopoietic stem cell transplantation, 23 we found that monocytes after hematopoietic stem cell transplantation were particularly sensitive to respond to an exposure to IFN-␥ with an accelerated release of tryptophan metabolite kynurenine, and, thus, to turn into suppressor cells. This finding suggested the possibility that an augmented IDO activity in recipients of a hemat...

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

“…This phenomenon is quite unusual [16], since IDO is often regarded as a feedback mechanism to inflammation, which may be indicated by proinflammatory cytokines [6,8]. However, this finding corroborates our concept that proinflammatory DC cytokine production and IDO induction are separate processes [6].…”

“…In our recent studies, we observed that strong IDO induction as a counterregulatory mechanism mediated APC activation [6,15], particularly when DCs were polarized by IFN-γ toward a DC1 phenotype [30,31]. Here, consistent with previous literature [25,26], we found that the cytokine and PGE 2 -matured DCs failed to produce the key cytokines characterizing a DC1 phenotype IL12p70 and IFN-γ [30,32] (Fig.…”

“…Thus, PGE 2 -matured DCs are similarly effective in induction of DC IDO activity as was recently shown for DCs exposed to lipopolysaccharide (LPS) and IFN-γ [6]. …”

“…IDO competence, i.e. IDO expression and activity [5,6], has been suggested to play a critical role in numerous clinical conditions entailing immune regulation, including tolerance induction in pregnancy [7], transplantation [8,9], and tumor immune evasion [10]. * These authors contributed equally to the work.…”

“…This phenomenon is quite unusual [16], since IDO is often regarded as a feedback mechanism to inflammation, which may be indicated by proinflammatory cytokines [6,8]. However, this finding corroborates our concept that proinflammatory DC cytokine production and IDO induction are separate processes [6]. The role of PGE 2 in directing DCs to exert an immune stimulatory or immune regulatory effect on T-cell responses, particularly with respect to PGE 2 -induced IDO induction in human DCs, has recently been controversially discussed.…”