The tolerogenic role of IFN-γ

Due to its extremely pleiotropic nature, the complex effects of IFN-γ exerted both on immune and non-immune cell types still remain only partially understood. The longstanding view of IFN-γ as being a predominantly inflammatory cytokine is constantly challenged by increasing demonstrations of its direct or indirect regulatory roles. Interferon-γ can exert tolerogenic effects on both innate and adaptive immune cell types, promoting tolerance of various antigen-presenting cells, and augmenting function and differentiation of regulatory T cells, respectively. Its capacity to induce IDO-competence is not limited to immune cells but extends to other cell types such as mesenchymal stem cells, epithelial cells, and tumors. The pro-inflammatory role of IFN-γ in tumor immune surveillance can backfire by directly inducing inhibitory molecule expression, such as PDL-1, on tumor cells. With increasing knowledge regarding the role of different helper T cell subsets in certain autoimmune diseases, the once contradictory observations of disease attenuation by IFN-γ can now be explained by its opposing interplay with other effector cytokines, particularly IL-17. The paradoxically immunosuppressive role of IFN-γ is also becoming evident in the transplantation setting, and graft-versus-host-disease. In the present review, we will discuss the latest findings that help to elucidate this dual role of IFN-γ at a cellular level, and in various pathophysiological states.