Expression of IFNγR2 mutated in a dileucine internalization motif reinstates IFNγ signaling and apoptosis in human T lymphocytes.
In T lymphocytes, the internalization of the R2 chain of the IFN-γ receptor (IFN-γR2) prevents the switching-on of pro-apoptotic and anti-proliferative genes induced by the IFN-γ/STAT1 pathway. In fibroblasts, a critical role of controlling the IFN-γR2 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-γR2 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-γ. In comparison with T cells that expressed wild-type IFN-γR2, cells that expressed the mutated receptor displayed, in response to IFN-γ 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-γ. Finally, lentiviral-mediated transduction of the mutated receptor in T lymphoblasts from healthy donors reinstated their IFN-γ-dependent apoptosis. As a whole, these data indicate that perturbation of IFN-γR2 internalization by mutating the LI(255-256) motif induces a timely coordinated activation of IFN-γ/STAT1 signaling pathways that leads to the apoptosis of T cells.
Boselli
Daniela
D
Center for Experimental Research and Medical Studies, San Giovanni Battista Hospital, University of Turin, 10126 Turin, Italy.
Ragimbeau
Josiane
J
Orlando
Luca
L
Cappello
Paola
P
Capello
Michela
M
Ambrogio
Chiara
C
Chiarle
Roberto
R
Marsili
Giulia
G
Battistini
Angela
A
Giovarelli
Mirella
M
Pellegrini
Sandra
S
Novelli
Francesco
F
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D019169:Jurkat Cells; D007930:Leucine / Q000235:genetics / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism; D000096743:Interferon gamma Receptor
D004151:Dipeptides; D053222:Fas Ligand Protein; D007371:Interferon-gamma; D007930:Leucine; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D019014:fas Receptor; D000096743:Interferon gamma Receptor