Expression of IFNgammaR2 mutated in a dileucine internalization motif reinstates IFNgamma signaling and apoptosis in human T lymphocytes.

摘要

In T lymphocytes, the internalization of the R2 chain of the IFN-gamma receptor (IFN-gammaR2) prevents the switching-on of pro-apoptotic and anti-proliferative genes induced by the IFN-gamma/STAT1 pathway. In fibroblasts, a critical role of controlling the IFN-gammaR2 internalization is played by the LI(255-256) intracellular motif. Here we show that, in human malignant T cells, the expression of a mutated IFN-gammaR2 chain in which the LI(255-256) internalization motif is replaced by two alanines (LI(255-256)AA) induces cell surface accumulation of the receptor and reinstates the cell sensitivity to IFN-gamma. In comparison with T cells that expressed wild-type IFN-gammaR2, cells that expressed the mutated receptor displayed, in response to IFN-gamma a sustained activation of STAT1. The activation of this signaling pathway leads to higher induction of MHC class I and FasL expression and triggered apoptosis. Malignant ST4 cells transduced with either wild-type or mutated receptor were able to grow in SCID mice, but only the proliferation of T cells expressing the mutated receptor was inhibited by IFN-gamma. Finally, lentiviral-mediated transduction of the mutated receptor in T lymphoblasts from healthy donors reinstated their IFN-gamma-dependent apoptosis. As a whole, these data indicate that perturbation of IFN-gammaR2 internalization by mutating the LI(255-256) motif induces a timely coordinated activation of IFN-gamma/STAT1 signaling pathways that leads to the apoptosis of T cells.