Gastrointestinal dendritic cells play a role in immunity, tolerance, and disease

Numerous mechanisms have been reported for DC suppression of T-cell immune responses. (A) Thymus-derived regulatory T cells (CD4+CD25+ Treg cells) can induce the production of indoleamine 2,3 dioxygenase (IDO) through CTLA-4-B7 via the induction of IFN-γ (a). IDO is an enzyme that exhibits immunomodulatory activity on T cells by catabolism of tryptophan (Trp), an essential amino acid for cellular proliferation. IDO is under the regulation of IFN-γ and can be induced by the presence of IFN-α, either from the DC themselves or from other sources (b). Prostaglandin E₂ (PGE₂) has been shown to down-regulate DC immunostimulatory function through increased production of IL-10. PGE₂ production by DC also down-regulates leukotriene B4 (LTB4), IL-12, and MHC Class II, thus resulting in down-regulation of immune responses. (B) Serrate1, a ligand for Notch1, can differentiate peripheral naı̈ve CD4+ T cells into regulatory cells. Suppression of cellular proliferation through transfer of Serrate1-induced regulatory T cells is antigen specific and induces down-regulation of IL-2 and IFN-γ in responding T cells. (C) IL-10, TGF-β, and IFN-α have all been implicated in the induction of T cells with regulatory properties. Regulatory T cells that mediate suppression of proliferative T cell responses, other than thymically derived CD4+CD25+ T regulatory cells, have been named Tr1 and Th3, based on their cytokine profiles. Tr1 cells produce IL-10 with little to no IL-4, whereas Th3 cells are defined as primarily TGF-β producers along with various amounts of IL-4 and IL-10. (D) The repetitive stimulation of naı̈ve CD4+ T cells with allogeneic immature DC can result in the generation of T cells with suppressive properties. These T cells proliferate poorly and induce high levels of IL-10; however, their inhibitor activity was found to be strictly cell-contact dependent. These immunosuppressive mechanisms of DC may not necessarily be mutually exclusive.