Regulation of human auto- and alloreactive T cells by indoleamine 2,3-dioxygenase (IDO)–producing dendritic cells: too much ado about IDO?

Abstract

Although dendritic cells (DCs) strongly stimulate the immune response, they can also induce unresponsiveness. Recently, a human monocyte-derived DC subpopulation was described that constitutively expresses indoleamine 2,3-dioxygenase (IDO). These DCs were defined as nonadherent CD123 ؉ /CC chemokine receptor 6 ؉ (CCR6 ؉ ) cells that suppress the allogeneic T-cell response. In the present study, we generated nonadherent, mature DCs from human blood monocytes. As expected, in addition to the classic markers, these cells expressed CD123 and CCR6. IntroductionSince 1998, when a series of brilliant mouse experiments 1 showed that a placental enzyme called indoleamine 2,3-dioxygenase (IDO) was able to prevent rejection of the fetus during pregnancy, the scientific community has been intrigued by a novel, basic immunoregulatory mechanism whose main player is IDO. Munn et al 1 presented a convincing experiment: they implanted time-release capsules containing the IDO inhibitor 1-methyl-tryptophan (1-MT) into pregnant mice bred to genetically different fathers. This treatment induced fetal rejection. The experimental design relied on the observation that, under certain circumstances, macrophages inhibit the T-cell response, apparently because they produce IDO, 2,3 an enzyme that is also manufactured in the placenta by the fetus-derived syncytiotrophoblast. 4 Based on their experimental findings, Munn et al forwarded the hypothesis that once the embryo implants and begins establishing connections with the mother's blood supply, fetal-derived cells located in the placenta begin making IDO. By destroying tryptophan-so went the speculation-IDO suppresses maternal T cells that otherwise would make their way through the placenta and attack the fetus.Subsequent studies addressed the mechanism by which tryptophan degradation affects the T-cell response and came to the conclusion that certain metabolites have a strong T-cell inhibitory action. 5,6 Among the tryptophan metabolites, 3-OH-kynurenine and 3-OH-anthranilic acid were shown to be strongly inhibitory, whereas kynurenine had a significant but weaker effect. 5 The mechanism that is able to efficiently regulate the immune reaction during pregnancy, a phenomenon of outstanding importance for the perpetuation of species, can be expected to be "used" by nature for controlling other unwanted immune reactions. A series of interesting studies emerged, shedding light on the mechanism of IDO up-regulation and its hypothetical role in immunoregulation. Most notable is the study of Grohmann et al 7 showing that cytotoxic T-lymphocyte antigen-4-immunoglobulin (CTLA4-Ig) up-regulates IDO in murine dendritic cells (DCs) by ligation to B7 molecules via induction of interferon-␥ (IFN-␥) synthesis. DCs from CTLA4-Ig-treated mice showed an increased rate of IDO production, suggesting that this mechanism also works in vivo. If murine IDO-producing DCs inhibit T-cell responses, as shown by some studies, 8,9 administration of the IDO inhibitor 1-MT would be expected to reverse CTLA4-Ig-induced ...

Extensive Profiling of the Expression of the Indoleamine 2,3-Dioxygenase 1 Protein in Normal and Tumoral Human Tissues

“…Our results are consistent with a range of published observations but do not confirm other reported concepts, such as the enrichment of IDO1 þ DCs in human TDLNs and the expression of IDO1 by CD123 þ plasmacytoid DCs (18,(20)(21)(22)(23). This latter observation has already been questioned by others (40,41). Our new antibody might be a helpful IHC tool in translational and clinical research, to test IDO1 expression in tumor samples to correctly assess its prognostic impact, select patients for IDO1 inhibitor therapy, and study the mechanisms of tumor response to such treatments.…”

Differential effects of the tryptophan metabolite3‐hydroxyanthranilic acid on the proliferation of human CD8+ T cells induced by TCR triggering or homeostatic cytokines

“…Importantly, these data are largely consistent with a recent report, mostly focusing on CD4 + cells, showing that IDO expressing DC are fully competent to stimulate allo-and soluble antigen-specific responses [20].…”

Mitomycin C-treated dendritic cells inactivate autoreactive T cells: Toward the development of a tolerogenic vaccine in autoimmune diseases

“…Human DCs were generated according to a standard protocol as previously described (11). Peripheral blood monocytes were cultured in the presence of 1000 units/ml rh IL-4 (Promocell, Heidelberg, Germany) and 666 units/ml rh GM-CSF (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany) in RPMI medium 1640 supplemented with 10% fetal calf serum (FCS), 2 mM L-glutamine, and penicillin (100 units/ml)/streptomycin (100 g/ml).…”

“…Human peripheral blood lymphocytes of MS patients were coincubated with autologous MBP-loaded DCs. In a parallel experiment, DRB1*0301-DCs from healthy donors were loaded with MBP and coincubated with MBP-specific CD4 ϩ T cells (clone ES-BP8T) as previously described (11). In a control experiment, the DCs were loaded with an irrelevant peptide with comparable interaction with DRB1*0301.…”