Type I and II IFNs differentially regulate IFNGR1 to tune IFNγ responsiveness in myeloid cells

Abstract

Abstract Interferons (IFNs) act on macrophages to shape immune responses against microbial infections and tumors. Type I and II IFNs signal to induce transcription of IFN-stimulated genes (ISGs). Binding of the type II IFN (IFNγ) to its receptor, IFNGR, induces ISGs that enhance macrophage inflammatory and anti-microbial activity critical for bacterial infection. Conversely, when type I IFNs bind their receptor (IFNAR), they reduce expression of myeloid cell surface IFNGR and dampen macrophage responsiveness to IFNγ. Macrophages stimulated with IFNγ also reduce cell surface IFNGR, but this was previously attributed to ligand-induced receptor internalization. Here, we confirm the ability of IFNγ stimulation to rapidly reduce cell surface IFNGR in cultured mouse and human macrophages. However, we find this ligand-induced reduction in IFNGR is associated with reduced ifngr1 transcript abundance. Unlike IFNβ, IFNγ did not impede de novo transcription from an ifngr1 promoter-driven reporter construct, suggesting IFNγ reduces ifngr1 transcript abundance via a distinct mechanism. BMDMs pulsed with IFNγ transiently became refractory to a secondary IFNγ treatment as measured by impaired STAT1 phosphorylation. As shown previously, type I IFNs cause a reduction in myeloid cell surface IFNGR1 seen 72 hpi with systemic L. monocytogenes (Lm), and this reduction was abrogated by myeloid cell expression of a transgenic IFNGR1 in fGR1 mice. In contrast, IFNγ was responsible for a reduction in IFNGR on myeloid cells early after systemic Lm infection (24 hip), and this was not abrogated in fGR1 mice. Together, our results demonstrate that type I and II IFNs act via distinct mechanisms to prevent hyper-activation of myeloid cells following exposure to IFNγ.