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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3214-3221.
Prepublished online as a Blood First Edition Paper on December 30, 2004; DOI 10.1182/blood-2004-07-2686.
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Submitted July 14, 2004
Accepted December 14, 2004
Iron regulates T lymphocyte sensitivity to the IFN- /STAT1 signaling pathway in vitro and in vivo
Gabriella Regis, Marita Bosticardo, Laura Conti, Stefania De Angelis, Daniela Boselli, Barbara Tomaino, Paola Bernabei, Mirella Giovarelli, and Francesco Novelli*
Center for Experimental Research and Medical Studies (CERMS), San Giovanni Battista Hospital-Molinette, Turin, Italy; Department of Medicine and Experimental Oncology, Section of Pathology, University of Turin, Turin, Italy
Department of Medicine and Experimental Oncology, Section of Pathology, University of Turin, Turin, Italy
Center for Experimental Research and Medical Studies (CERMS), San Giovanni Battista Hospital-Molinette, Turin, Italy
* Corresponding author; email: franco.novelli{at}unito.it.
The refractoriness of T cells to the Interferon (IFN)- /Signal Transducer and Activator of Transcription (STAT) 1 pathway, which shields them from the antiproliferative effect of IFN-, is mainly attributed to downregulation of the IFN-R2 signaling chain. However, the mechanisms responsible for this downregulation are unclear. Here we show that iron uptake mediated by the transferrin receptor (TfR) delivers a signal that leads to IFN-R2 internalization and thus plays an essential role in attenuating activation of the IFN-/STAT1 pathway in human T lymphocytes. The effect of iron on IFN-R2 internalization was specific as it did not affect expression of the IFN-R1 binding chain. Deferoxamine (DFO), an iron-chelating agent, upregulated IFN-R2 surface expression and reinstated IFN-/STAT1 activation in proliferating T lymphocytes. Resistance of malignant T cells to the antiproliferative effect of IFN- in vitro was abrogated by addition of DFO. Conversely, iron inhibited IFN--induced apoptosis in malignant T cells in serum-free conditions. In combination but not individually, DFO and IFN- strongly inhibited growth of human malignant T cells in an in vivo SCID mouse model. These data provide valuable insights for novel therapeutic approaches aimed at reinstating the IFN-/STAT1 apoptotic signaling pathway in autoreactive or neoplastic T cells by means of iron chelation.
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