Iron regulates T-lymphocyte sensitivity to the IFN-gamma/STAT1 signaling pathway in vitro and in vivo.
The refractoriness of T cells to the interferon-gamma (IFN-gamma)/signal transducer and activator of transcription 1 (STAT1) pathway, which shields them from the antiproliferative effect of IFN-gamma, is attributed mainly to down-regulation of the IFN-gammaR2 signaling chain. However, the mechanisms responsible for this down-regulation are unclear. Here we show that iron uptake mediated by the transferrin receptor (TfR) delivers a signal that leads to IFN-gammaR2 internalization and thus plays an essential role in attenuating activation of the IFN-gamma/STAT1 pathway in human T lymphocytes. The effect of iron on IFN-gammaR2 internalization was specific as it did not affect expression of the IFN-gammaR1 binding chain. Deferoxamine (DFO), an iron-chelating agent, up-regulated IFN-gammaR2 surface expression and reinstated IFN-gamma/STAT1 activation in proliferating T lymphocytes. Resistance of malignant T cells to the antiproliferative effect of IFN-gamma in vitro was abrogated by addition of DFO. Conversely, iron inhibited IFN-gamma-induced apoptosis in malignant T cells in serum-free conditions. In combination but not individually, DFO and IFN-gamma strongly inhibited growth of human malignant T cells in an in vivo severe combined immunodeficient (SCID) mouse model. These data provide valuable insights for novel therapeutic approaches aimed at reinstating the IFN-gamma/STAT1 apoptotic signaling pathway in autoreactive or neoplastic T cells by means of iron chelation.
Regis
Gabriella
G
Laboratory of Tumor Immunology, CERMS, San Giovanni Battista Hospital-Molinette, Via Santena 5, I-10126 Turin, Italy.
Bosticardo
Marita
M
Conti
Laura
L
De Angelis
Stefania
S
Boselli
Daniela
D
Tomaino
Barbara
B
Bernabei
Paola
P
Giovarelli
Mirella
M
Novelli
Francesco
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism*; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D019169:Jurkat Cells; D051379:Mice; D016513:Mice, SCID; D017471:Receptors, Interferon / Q000378:metabolism; D011990:Receptors, Transferrin / Q000037:antagonists & inhibitors; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D000096743:Interferon gamma Receptor
D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D007501:Iron; D007502:Iron Chelating Agents; D017471:Receptors, Interferon; D011990:Receptors, Transferrin; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse