IFN‐γ‐rich environment programs dendritic cells toward silencing of cytotoxic immune responses. Issue 1 (7th August 2013)

• Record Type: Journal Article
• Authors: Švajger, Urban; Obermajer, Nataša; Jeras, Matjaž
• Is Part Of: Journal of leukocyte biology. Volume 95:Issue 1(2014)
• Page Start: 33
• Page End: 46
• Publication Date: 2013-08-07
• Subjects: immune regulation -- inflammation -- homeostasis; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.1112589
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : The unexplored potential of DC regulation by high dose IFN‐γ, with novel mechanisms of immune regulation within a peak inflammatory environment. Abstract : 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.