IDO: a double-edged sword for T(H)1/T(H)2 regulation

Abstract

Indoleamine 2,3-dioxygenase (IDO) has been well defined as one of the important immunosuppressive properties for T(H)1 cell-mediated immune responses, but its function in T(H)2 dominant system is poorly understood. Recently, an appreciable number of publications suggest that the role of IDO in T(H)2 cell regulation may be different from that of T(H)1 immune responses. Here we review the evidence on the regulatory function of IDO and tryptophan metabolites in T(H)1/T(H)2 differentiation. We propose that IDO-kynurenine pathway can serve as a negative feedback loop for T(H)1 cells but it may play a distinct role in up-regulating T(H)2 dominant immune responses.

Figure 1

Dynamics of antigen-induced cell immune responses: a. IDO expression and its influence on T helper cell differentiation. DCs uptake antigen and activate naïve T cells to initiate T helper cell differentiation. IFN-γ production from DCs and bystander NK cells will skew T_H0 cells into the T_H1 pathway. Polarized T_H1 cells produce IFN-γ, which subsequently suppresses T_H2 differentiation and induces DCs to express functional IDO. The increase in IDO expression will inhibit proliferation of T_H1 cells and release T_H2 cells from suppression by T_H1. In the meantime, IDO will directly induce the development of T_H2 cells, which leads to an enhanced T_H2 response. In addition, IDO also induces the generation of regulatory T cells, which further limit both T_H1 and T_H2 responses. b. Kinetics of T cell responses and IDO expression. Antigen stimulation initiates T_H1 response followed by an increasing IDO expression. As IDO climbs to high levels, T_H1 response will decline, which is accompanied by enhanced T_H2 response. As IDO-induced Treg cell responses occur, Treg cells will inhibit both T_H1 and T_H2 cells and bring the immune system close to physiological balance.