IDO, an enzyme that degrades the essential amino acid tryptophan, can be synthesized by many cell types. IDO-expression is essential to maintain pregnancy as IDO-deficiency or pharmacological inhibition of IDO results in rapid T cell-induced rejection of allogeneic concepti, but is also involved in the control of many other immunological processes, such as tumor resistance, chronic infection, autoimmunity and allergic inflammation [6]. During an immune response, it can be expressed in response to, for example, interferon-γ, and thereby is thought to protect the host from collateral damage by suppressing T-cell responses [6]. The immune regulatory function of IDO has been attributed mainly to the reduction of local tryptophan concentration and the generation of tryptophan metabolites [6].
The article by Park and colleagues now shows that IDO can also promote tolerance to orally administered collagen type II in mice [1]. CD11c+DCs in Peyer's patches from orally tolerized mice exhibit an immature phenotype and express higher levels of IDO compared to those from control mice. Functionally, they inhibit collagen type II-specific T cell proliferation and pro-inflammatory Th1 cytokine production, and more importantly, induce the generation of collagen type II-specific CD4+CD25+FOXP3+ Treg cells from highly purified CD4+CD25- T cells in an IDO-dependent manner. Notably, the generation of Treg cells is antigen specific, as IDO-expressing DCs without antigen have no effect [1]. These data are in line with recent findings showing that IDO-expressing DCs can also directly activate resting CD4+CD25+FOXP3+ Treg cells for potent suppressor activity [7], and that cytotoxic T-lymphocyte antigen-4 and glucocorticoid-inducible tumor necrosis factor receptor-related protein, molecules highly expressed on CD4+CD25+ Treg cells, can induce IDO expression in DCs [8]. Together, these results indicate that IDO-producing DCs and CD4+CD25+ Treg cells may form a positive feedback loop in the induction of oral tolerance [1, 7, 8].
However, although the combined effects of tryptophan starvation and tryptophan catabolites may contribute to the induction of CD4+CD25+Treg cells by IDO [9], the position of IDO in the induction of oral tolerance remains to be determined. Notably, recent reports showing that retinoic acid, a metabolite of vitamin A, produced by CD103+ DCs in mesenteric lymph nodes promotes oral tolerance by enhancing the transforming growth factor-β-dependent conversion of naïve T cells into Treg cells [10] are of interest and pose the question whether different subtypes of DCs (CD103 positive versus negative) or DCs located at different places of the gut (mesenteric lymph nodes versus Peyer's patches) use different mechanisms (retinoic acid versus IDO) to induce Treg cells. Furthermore, the relative contribution of these two pathways in the induction of oral tolerance to defined antigens remains to be determined.