In the absence of IGF-1 signaling, IFN-gamma induces T cell apoptosis (94.14)

Abstract

Abstract IFNg exerts its biological activities by interacting with its cell surface receptor (IFNgR), which consists of two binding chains (R1) and two signal transducing chains (R2).The binding of IFNg to its receptor complex activates the JAK/STAT signal transduction pathway and induces the transcription of IFNg-inducible apoptotic genes. T cells that undergo Th1 polarization or malignant transformation become resistant to the antiproliferative effects of the IFNg/STAT1 pathway.This refractoriness is mainly due to R2 downregulation, due to ligand-independent internalization within clathrin-coated pits. We have previously demonstrated that, by inducing R2 internalization, IGF1 is a critical factors in limiting the IFNg/STAT1 pathway in T cells. Thus, the blockade of its signaling in T cells could hinder their intracellular R2 trafficking and reinstate their sensitivity to IFNg/STAT1 apoptotic signaling. To address this point, a retrovirus-based approach was exploited to stably express a dominant negative form of the IGF1R (IGF1R DN) in ST4 T cell line. Expression of IGF1R DN induced R2 cell surface accumulation and reinstated ST4 cell sensitivity to the IFNg/STAT1 apoptotic pathway in vitro and in vivo. Moreover, the combined exposure to an inhibitor of IGF1R tyrosine kinase activity (picropodophyllin, PPP) and IFNg induced STAT1-dependent apoptosis of three T cell lines (Jurkat ST4 and PF382).These results could be used in the elaboration of new therapeutic approaches based on IGF1 signaling blockade to overcome the resistance of malignant or autoreactive T cells to the apoptotic effect of IFNg.