IFNγR2 trafficking tunes IFNγ–STAT1 signaling in T lymphocytes

Ligand-dependent downregulation of the interferon γ receptor signaling chain (IFNγR2) has always been seen as a key mechanism for shielding T lymphocytes from the antiproliferative effects of the IFNγ–signal transducer and activator of transcription 1 (STAT1) pathway. Now, however, a ligand-independent mechanism of IFNγR2 internalization is emerging as a more general way of limiting IFNγ–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 IFNγR2 cell-surface accumulation and IFNγ-induced apoptosis in T cells, whereas an anti-inflammatory environment promotes IFNγR2 internalization and induces T cell unresponsiveness to IFNγ signaling.