IFN-γ-rich environment programs dendritic cells toward silencing of cytotoxic immune responses

Lately, there is increasing evidence that emphasizes the regulatory functions of IFN-γ, which serve as negative-feedback mechanisms after, e.g., pathogen clearance, to prevent unnecessary tissue destruction. Inflammatory processes involving Th1 and cytotoxic responses are characterized by high, local IFN-γ concentrations, followed by resolution and immune silencing. Although this is a well-known course of events, extensive attempts to address potential differential effects of IFN-γ in the manner of its availability (quantitatively) in the environment do not exist. We demonstrate that high doses of IFN-γ do not induce DC maturation and activation but instead, induce specific regulatory characteristics in DCs. Considering their phenotype, high doses of IFN-γ extensively induce the expression of ILT-4 and HLA-G inhibitory molecules. Interestingly, the well-known priming effect of IFN-γ for IL-12p70 production is lost at these conditions, and the DC cytokine profile is switched toward an increased IL-10/IL-12p70 ratio upon subsequent stimulation with CD40L. Furthermore, such DCs are capable of silencing cellular immune responses and activation of cytotoxic CD8+ T lymphocytes, resulting in reduced cell proliferation and down-regulation of granzyme B expression. Additionally, we find that in this manner, immune regulation mediated by IFN-γ is not mainly a result of increased enzymatic activity of IDO in DCs but rather, a result of HLA-G signaling, which can be reversed by blocking mAb. Altogether, our results identify a novel mechanism by which a Th1-like environment programs the functional status of DCs to silence ongoing cytotoxic responses to prevent unwanted tissue destruction and inflammation.