IFNγR2 trafficking tunes IFNγ-STAT1 signaling in T lymphocytes

Ligand-dependent downregulation of the interferon gamma receptor signaling chain (IFN gamma R2) has always been seen as a key mechanism for shielding T lymphocytes from the antiproliferative effects of the IFN gamma-signal transducer and activator of transcription 1 (STAT1) pathway. Now, however, a ligand-independent mechanism of IFN gamma R2 internalization is emerging as a more general way of limiting IFN gamma-STAT1 signaling in T cells, with insulin-like growth factor-1 (IGF-1) and iron as the main players. Here, we review the array of immunomodulatory effects exerted by these two factors on different cell types involved in the immune response; these effects suggest that an inflammatory environment generates signals that favor IFN gamma R2 cell-surface accumulation and IFN gamma-induced apoptosis in T cells, whereas an anti-inflammatory environment promotes IFN gamma R2 internalization and induces T cell unresponsiveness to IFN gamma signaling.