Ligand-dependent downregulation of the interferon gamma receptor signaling chain (IFNgammaR2) has always been seen as a key mechanism for shielding T lymphocytes from the antiproliferative effects of the IFNgamma-signal transducer and activator of transcription 1 (STAT1) pathway. Now, however, a ligand-independent mechanism of IFNgammaR2 internalization is emerging as a more general way of limiting IFNgamma-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 IFNgammaR2 cell-surface accumulation and IFNgamma-induced apoptosis in T cells, whereas an anti-inflammatory environment promotes IFNgammaR2 internalization and induces T cell unresponsiveness to IFNgamma signaling.