IFNγR2 trafficking tunes IFNγ–STAT1 signaling in T lymphocytes

Regis, Gabriella; Conti, Laura; Boselli, Daniela; Novelli, Francesco

doi:10.1016/j.it.2005.12.002

Cited by 42 publications

(33 citation statements)

References 73 publications

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“…We have demonstrated that IFN-gR2 downregulation in T cells mainly results from its endocytosis that can be induced, independently from IFN-g, by iron and IGF-1 (4,12). Therefore, it is likely that the upregulation of IFN-gR2 we observed in activated Th17 cells from MS patients results from the mobilization of IFN-gR2 from intracellular stores to the cell surface (4). Upon in vitro activation, Th1 and Th17 cells displayed similar total protein levels of IFNgR2, even if Th17 cells expressed higher levels of mRNA at later times of culture.…”

Section: Discussionmentioning

confidence: 87%

“…Iron is increased in the brains of MS patients (22) and iron chelation ameliorates EAE (23). This suggests that strategies aimed to perturb IFN-gR2 intracellular traffic, such as iron chelation or IGF-1 signaling blockade (4,11), could enhance the predisposition to IFN-g-induced apoptosis in autoreactive Th17 cells. In MS, this approach can be used to synergize with IFN-b treatment that selectively inhibits Th17 cells (1).…”

Section: Discussionmentioning

confidence: 99%

“…The IFN-g/STAT1 pathway is predominantly activated in naive and Th2 cells expressing the IFN-gR2 signaling chain. Those cells are thus sensitive to the antiproliferative effect of IFN-g, whereas Th1 cells, which do not express this chain, are resistant (4).…”

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confidence: 99%

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Th17 Cells in Multiple Sclerosis Express Higher Levels of JAK2, Which Increases Their Surface Expression of IFN-γR2

Conti

Palma

Rolla

et al. 2012

The Journal of Immunology

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IFN-β inhibits the expansion of Th17 cells in active multiple sclerosis (AMS), and this might contribute to improve the clinical symptoms. The effectiveness of this inhibition, however, requires intact IFN-γ signaling in T cells. In this study, we report that both mRNA and cell surface expression of the signaling chain of the IFN-γ receptor (IFN-γR2) and its cognate tyrosine kinase JAK2 are enhanced in peripheral blood Th17 cells and clones from patients with AMS compared with those with inactive multiple sclerosis (IMS) or healthy subjects (HS). IFN-γ decreased the frequency of Th17 peripheral cells and proliferation of Th17 clones from AMS patients. Stimulation of PBMCs from HS in Th17-polarizing conditions resulted in the enhancement of JAK2 expression and accumulation of cell surface IFN-γR2. The role of JAK2 in the modulation of IFN-γR2 was demonstrated as its transduction prevented rapid internalization and degradation of IFN-γR2 in JAK2-deficient γ2A cells. In conclusion, these data identify JAK2 as a critical factor that stabilizes IFN-γR2 surface expression in Th17 cells from AMS patients, making them sensitive to IFN-γ. These data may have clinical implications for a better use of IFNs in multiple sclerosis and possibly other inflammatory diseases.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Th17 Cells in Multiple Sclerosis Express Higher Levels of JAK2, Which Increases Their Surface Expression of IFN-γR2

Conti

Palma

Rolla

et al. 2012

The Journal of Immunology

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“…22 In human neoplastic T cells, this pathway is impaired because of the downregulated expression of the IFN-gR2 signaling chain. 13 Starting from the observation that in STAT3 À/À mouse embryonic fibroblasts IL-6 acquires the completely new ability to mediate an IFN-g-like response due to prolonged STAT1 activation, 3 we decided to assess whether a similar phenomenon may also occur in human neoplastic T lymphocytes, leading to bypass their block in IFN-g signaling. Our data show that, indeed, the responses to IL-6 can be driven towards STAT1 activation and STAT1-mediated functions by interfering with STAT3 in human neoplastic T lymphocyte cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 In particular, in human neoplastic T cells, IFN-g unresponsiveness is often due to constitutive internalization of the transducing IFN-gR2 chain. 13 In an attempt to bypass this unresponsiveness, we thus decided to analyze the consequences of abolishing STAT3 expression in human neoplastic T cells in terms of re-activation of the STAT1-mediated apoptotic pathway. We thus stably knocked down STAT3 in two human neoplastic T cell lines, ST4 and Molt4, and investigated the effects of both IFN-g and IL-6 treatment.…”

Section: Introductionmentioning

confidence: 99%

IL-6, but not IFN-γ, triggers apoptosis and inhibits in vivo growth of human malignant T cells on STAT3 silencing

et al. 2009

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STAT1 and STAT3 are the main mediators of the signaling of interferons (IFNs) and of gp130 cytokines, respectively. Neoplastic T lymphocytes frequently become resistant to the IFN-c/ STAT1 apoptotic pathway, often because of the downregulation of the IFN-cR2 receptor chain. Many studies suggest that crossregulation between different STATs, in particular between STAT1 and STAT3, may profoundly affect cytokine/growth factor signaling. Here, the function of STAT3 in the negative regulation of STAT1 apoptotic pathway was investigated by RNA interference-mediated STAT3 silencing in human malignant T lymphocytes. In STAT3-depleted cells, interleukin (IL)-6 acquired the capacity to induce apoptosis, correlating with prolonged STAT1 activation and the induction of major histocompatibility complex (MHC) class I expression. In contrast, in the absence of STAT3, IFN-c could slightly enhance apoptosis but its ability to induce MHC class I expression was unchanged. Accordingly, IL-6, but not IFN-c, could significantly impair the in vivo growth of STAT3-depleted human neoplastic T lymphocytes transplanted into severe combined immunodeficient mice. Therefore, treatment with IL-6 and simultaneous STAT3 silencing may represent a potential therapeutic approach to control the expansion of IFN-c-unresponsive neoplastic T cells.

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T‐helper 17 cells expand in multiple sclerosis and are inhibited by interferon‐β

Durelli

Conti

Clerico

et al. 2009

Annals of Neurology

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IFNγR2 trafficking tunes IFNγ–STAT1 signaling in T lymphocytes

Cited by 42 publications

References 73 publications

Th17 Cells in Multiple Sclerosis Express Higher Levels of JAK2, Which Increases Their Surface Expression of IFN-γR2

Th17 Cells in Multiple Sclerosis Express Higher Levels of JAK2, Which Increases Their Surface Expression of IFN-γR2

IL-6, but not IFN-γ, triggers apoptosis and inhibits in vivo growth of human malignant T cells on STAT3 silencing

T‐helper 17 cells expand in multiple sclerosis and are inhibited by interferon‐β

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