Iron regulates T-lymphocyte sensitivity to the IFN-γ/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, Francesco Novelli

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The refractoriness of T cells to the interferon-γ (IFN-γ)/signal transducer and activator of transcription 1 (STAT1) pathway, which shields them from the antiproliferative effect of IFN-γ, is attributed mainly to down-regulation of the IFN-γR2 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-γR2 internalization and thus plays an essential role in attenuating activation of the IFN-γ/STAT1 pathway in human T lymphocytes. The effect of iron on IFN-γR2 internalization was specific as it did not affect expression of the IFN-γR1 binding chain. Deferoxamine (DFO), an iron-chelating agent, up-regulated IFN-γR2 surface expression and reinstated IFN-γ/STAT1 activation in proliferating T lymphocytes. Resistance of malignant T cells to the antiproliferative effect of IFN-γ in vitro was abrogated by addition of DFO. Conversely, iron inhibited IFN-γ-induced apoptosis in malignant T cells in serum-free conditions. In combination but not individually, DFO and IFN-γ 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-γ/STAT1 apoptotic signaling pathway in autoreactive or neoplastic T cells by means of iron chelation.

Original languageEnglish
Pages (from-to)3214-3221
Number of pages8
JournalBlood
Volume105
Issue number8
DOIs
Publication statusPublished - Apr 15 2005

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STAT1 Transcription Factor
T-cells
Interferons
Iron
T-Lymphocytes
Deferoxamine
In Vitro Techniques
Down-Regulation
Chemical activation
Iron Chelating Agents
Transferrin Receptors
SCID Mice
Chelation
Transcriptional Activation

ASJC Scopus subject areas

  • Hematology

Cite this

Regis, G., Bosticardo, M., Conti, L., De Angelis, S., Boselli, D., Tomaino, B., ... Novelli, F. (2005). Iron regulates T-lymphocyte sensitivity to the IFN-γ/STAT1 signaling pathway in vitro and in vivo. Blood, 105(8), 3214-3221. https://doi.org/10.1182/blood-2004-07-2686

Iron regulates T-lymphocyte sensitivity to the IFN-γ/STAT1 signaling pathway in vitro and in vivo. / Regis, Gabriella; Bosticardo, Marita; Conti, Laura; De Angelis, Stefania; Boselli, Daniela; Tomaino, Barbara; Bernabei, Paola; Giovarelli, Mirella; Novelli, Francesco.

In: Blood, Vol. 105, No. 8, 15.04.2005, p. 3214-3221.

Research output: Contribution to journalArticle

Regis, G, Bosticardo, M, Conti, L, De Angelis, S, Boselli, D, Tomaino, B, Bernabei, P, Giovarelli, M & Novelli, F 2005, 'Iron regulates T-lymphocyte sensitivity to the IFN-γ/STAT1 signaling pathway in vitro and in vivo', Blood, vol. 105, no. 8, pp. 3214-3221. https://doi.org/10.1182/blood-2004-07-2686
Regis G, Bosticardo M, Conti L, De Angelis S, Boselli D, Tomaino B et al. Iron regulates T-lymphocyte sensitivity to the IFN-γ/STAT1 signaling pathway in vitro and in vivo. Blood. 2005 Apr 15;105(8):3214-3221. https://doi.org/10.1182/blood-2004-07-2686
Regis, Gabriella ; Bosticardo, Marita ; Conti, Laura ; De Angelis, Stefania ; Boselli, Daniela ; Tomaino, Barbara ; Bernabei, Paola ; Giovarelli, Mirella ; Novelli, Francesco. / Iron regulates T-lymphocyte sensitivity to the IFN-γ/STAT1 signaling pathway in vitro and in vivo. In: Blood. 2005 ; Vol. 105, No. 8. pp. 3214-3221.
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